Angiotensin 1-7

ACE2 Mediated Cardiac Fibrosis Alleviation Through Angiotensin-(1-7)/Mas Axis Regulation of the Renin-Angiotensin System/Rac Signaling Pathway.

Lili Zou, He Zhang, Jinqi Fan +3 more

This study aimed at investigating whether Angiotensin-(1-7) [Ang-(1-7)] could alleviate cardiac fibrosis by modulating the expression of Rac1 and Rad GTPase and evaluating the specific mechanism in rat cardiac fibroblasts (CFs) and in canine atrial rapid pacing models. Fresh CFs were isolated from ventricles of 1 ~ 3 day-old Sprague-Dawley rats, and were randomly divided into control group, LPS group, Ang-(1-7) group and LPS+Ang-(1-7) group. CCK8 was used to detect cell proliferation. qRT-PCR was to detect the mRNA expression of ACE2. Mongrel dogs were randomized into four groups: Sham-operated (Sham), AF-Control, AF-EGFP and AF-ACE2 groups. Immunoperoxidase staining was used to test Rac1 and Gem expression. Collagen fibers in heart were stained a red color and extent of cardiac fibrosis was evaluated. Histopathology was to observe actin,α-smooth. Enzyme-Linked Immunosorbent Assay was to detect Ang II and Ang-(1-7) expression in canine atrial tissue. And western blot analysis was to detect the protein expression of iNOS, COX2, α-SMA, Rac1, ACE, and AT1R in cells and tissues. Cellular experiments showed LPS promoted proliferation of fibroblasts, which could be inhibited by Ang-(1-7) (p < 0.05). Compared with control group, LPS-induced CFs showed a significant increase in protein expression of iNOS, COX2, and α-SMA, which promoted cell proliferation. However, the application of Ang-(1-7) reversed these effects and suppressed the ACE/AT1R signaling pathway in LPS-induced CFs. In animal experiments, ACE2 over-expression would up-regulate atrial Ang-(1-7) and AT2R and reduce atrial angiotensin II (Ang II) and AT1R expressions (p < 0.05). In AF-ACE2 group, Rac1 was down-regulated and Rad GTPase was up-regulated, in comparison with AF-Control and AF-EGFP groups, associated with reductions of CTGF, fibrosis-related factors α-SMA and N-cadherin. ACE2 was found to alleviate cardiac fibrosis through the Ang(1-7)/Mas signaling pathway in animal experiments.

Bifunctional Peptide Amphiphile Hydrogel Orchestrates Concerted Antioxidant and Anti-Inflammatory Actions to Counter Myocardial Ischemia/Reperfusion Injury.

Yuanyuan Wu, Siman Luo, Guanghui Xu +8 more

Myocardial ischaemia/reperfusion injury presents significant clinical challenges driven by a self-perpetuating cycle of oxidative stress and inflammation. Current therapeutic strategies fail to simultaneously address these interconnected pathological events. Here, we present T&A-Gel, a supramolecular peptide amphiphile hydrogel integrating α-tocopherol and Angiotensin-(1-7) (Ang-(1-7)) through covalent conjugation to enable localized co-delivery and synergistically disrupt this oxidative-inflammatory feed-forward circuit. Upon hierarchical self-assembly into filamentous nanofibres, T&A-Gel forms a sustained-release depot that exposes Ang-(1-7) moieties while sequestering hydrophobic α-tocopherol. This design enables α-tocopherol to scavenge excess reactive oxygen species, ameliorating oxidative mitochondrial dysfunction and reducing cardiomyocyte apoptosis, while exposed Ang-(1-7) acts as a selective Mas receptor (MasR) agonist, activating the protective MasR/PI3K/Akt signaling axis. This dual-action mechanism suppresses NF-κB nuclear translocation and inhibits pro-inflammatory cytokine cascades. In vitro, T&A-Gel significantly enhanced hypoxia/reoxygenation-injured cardiomyocyte viability. In vivo, T&A-Gel demonstrated prolonged retention with substantial reduction in infarct size and cardiac necrosis biomarkers. Quantitative analysis confirmed substantial attenuation of interstitial fibrosis and cardiomyocyte hypertrophy, translating into restored ejection fraction and reduced ventricular dilation with excellent biocompatibility. These findings establish injectable supramolecular hydrogels as a powerful strategy for disrupting the interconnected injury cascade via mechanistically complementary payloads, offering a paradigm for precision cardioprotection.

Saikosaponin D protects against isoproterenol-induced kidney injury in rats by regulating the intrarenal renin-angiotensin system.

Xiaoli Yi, Shanshan Song, Huiru Yang +3 more

Saikosaponin D (SSD), a triterpene saponin isolated from Bupleurum falcatum, exhibits diverse pharmacological activities and has been shown to alleviate kidney-related diseases in rodent models. However, its effects on isoproterenol (ISO)-induced kidney injury and the underlying mechanisms have not been fully elucidated. Herein, SSD administration effectively mitigated ISO-induced kidney injury in Sprague-Dawley rats, as evidenced by improvements in renal function parameters (e.g., reduced plasma creatinine and blood urea nitrogen) and histopathological structure. Specifically, SSD significantly suppressed ISO-induced upregulation of inflammatory cytokines, fibrotic markers, and kidney injury biomarkers in renal tissues. SSD treatment downregulated renal expression of angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE), reduced renal ACE activity and urinary angiotensin II (AngII) excretion, and upregulated renal angiotensin-converting enzyme 2 (ACE2) activity (without altering its expression) while increasing urinary angiotensin 1-7 (Ang1-7) excretion. Notably, no significant changes in plasma AngII or Ang1-7 concentrations were observed, indicating SSD specifically modulates the intrarenal renin-angiotensin system. Functional validation experiments showed that co-administration of SSD with the ACE inhibitor enalapril or AngII type 1 receptor (AT1R) antagonist losartan further potentiated its protective effects against ISO-induced kidney injury. In contrast, co-treatment with the ACE2 inhibitor MLN-4760 or Mas receptor (MasR) antagonist A779 completely abrogated SSD's renoprotective effects. In conclusion, our findings demonstrate that SSD exerts renoprotective effects against ISO-induced kidney injury by inhibiting renal fibrosis and inflammation. Mechanistically, SSD shifts the intrarenal RAS balance from the pro-inflammatory/fibrotic ACE/AngII/AT1R axis to the protective ACE2/Ang1-7/MasR axis, providing a novel therapeutic target for ISO-related kidney damage.

An Explorative Approach to Examining the Role of Ischemia and Inflammation on the Function of Autoantibodies Against G Protein-Coupled Receptors and Their Corresponding Agonists.

Gerd Wallukat, Petra Lakatos, Kira Steinhorst +2 more

Autoantibodies (AAbs) play an important role in the development of autoimmune diseases. While many AAbs induce apoptosis of target cells, a distinct subgroup, termed functional autoantibodies (fAAbs) against G protein-coupled receptors (GPCRs), can modulate physiological receptor signaling without inducing cell death. The functional activity of GPCR-fAAbs may be influenced by various cofactors, including inflammation (e.g., inflammatory cytokine, ciliary neurotrophic factor (CNTF)) and ischemia. As ischemia triggers a substantial release of arachidonic acid (AA) from membrane phospholipids, the present study aimed to examine exploratively the influence of AA, eicosapentaenoic acid (EPA), and CNTF on the responses of spontaneously beating neonatal rat cardiomyocytes to GPCR agonists and GPCR-fAAbs. AA and EPA differentially influenced responses in cardiomyocytes induced by GPCR-fAAbs: AA altered the functional responses associated with adrenergic β2-fAAb, adrenergic α1-fAAb, angiotensin II (AT1)-fAAb, endothelin A (ETA)-fAAb and angiotensin 1-7 MAS-fAAbs. However, muscarinergic M2-fAAb responses remained largely unaffected. In contrast, EPA attenuated the responses to β2-fAAb, α1-fAAb, AT1-fAAb, and ETA-fAAb, while MAS-fAAb and M2-fAAb responses were not markedly altered. CNTF acted as a time-dependent modulator of cardiomyocyte chronotropic responses and influenced the magnitude of GPCR-mediated signaling on a cardiomyocyte bioassay. Together, these findings might suggest that lipid mediators such as AA and EPA or CNTF may modulate functional responses of cardiomyocytes associated with GPCR-fAAbs.

Angiotensin-(1-7) Alleviates Isoproterenol-Induced Cardiac Hypertrophy by Suppressing Autophagy and Apoptosis Through the Synergistic Action of Mas Receptor and Angiotensin II Type 2 Receptor.

Xiaomei Wang, Fei Guo, Xiaoqian Wang +4 more

The aim of this study is to determine whether Angiotensin-(1-7) [Ang-(1-7)] alleviates isoproterenol (ISO)-induced cardiac hypertrophy by suppressing excessive autophagy and apoptosis through coordinated Mas receptor (MasR) and angiotensin II type-2 receptor (AT2R) signaling, and to elucidate the underlying mechanisms.

Mas Knockout Mice Present Altered Behavioral and Neuroendocrine Coping Responses to Chronic Unpredictable Stress.

Sthéfanie C A Gonçalves, Andressa da Silveira Silva, Bruna Karen Oliveira Nogueira +6 more

Stress is defined as a disruption of homeostasis that elicits adaptive responses aimed at restoring physiological balance. However, when stress becomes chronic or overwhelming, maladaptive changes may occur, contributing to endocrine, behavioral, and neuropsychiatric dysfunctions. Beyond the classical neuroendocrine axes, such as the sympatho-adrenomedullary and hypothalamic-pituitary-adrenal (HPA) axes, the renin-angiotensin system has also being implicated in stress modulation. Previous studies have shown that angiotensin-(1-7), acting through its receptor Mas, exerts a modulatory effect on the stress response, attenuating anxiety- and depression-like behaviors induced by various stressors. Here we investigated the impact of genetic deletion of Mas on the consequences of chronic unpredictable stress (CUS) exposure. Over 21 consecutive days, mice were subjected to random stressors, after which endocrine, behavioral and neurochemical assessments were performed. Mas knockout (KO) mice exposed to CUS exhibited significantly elevated corticosterone and blood glucose levels compared to stressed wild-type mice. In behavioral tests, stressed Mas KO mice displayed the highest immobility times in the forced swimming test, indicating enhanced depressive-like behavior. Anxiety-like behavior was also heightened in Mas KO mice, as evidenced by a significant reduction in the percentage of time spent in the open arms of the elevated plus maze test. Neurochemical analysis revealed a marked reduction in brain-derived neurotrophic factor (BDNF) levels in key brain regions of stressed Mas KO animals. Together, these findings suggest that Mas plays a critical role in the neurobiology of stress, since its absence exacerbates HPA axis hyperactivity, depression- and anxiety-like behaviors, as well as BDNF reduction. Overall, these results highlight the potential neuroprotective role of Mas in stress-related disorders.

The Counter-Regulatory Renin-Angiotensin System: A Surprising Ally in the Field of COVID-19.

Mariali Palacios-Cruz, Jairo Castellar-Lopez, Juan Manuel Pretelt +2 more

Over the past four years, SARS-CoV-2 and COVID-19 have become global health crises, spurring extensive research on virus behavior, complications, and treatments. The virus interacts with a component of the renin-angiotensin system (RAS), altering inflammatory, hypertrophic, and hemodynamic responses via binding to ACE2 found in organs like the heart, lungs, and kidneys.

The joint-local renin-angiotensin system in rheumatoid arthritis and osteoarthritis: mechanistic evidence, disease-specific patterns, and translational perspectives.

Emre Bilgin, İbrahim C Haznedaroğlu

The renin-angiotensin system (RAS), traditionally regarded as a hormonal cascade regulating cardiovascular and renal homeostasis, is increasingly recognized as a locally active, tissue-specific network within joint structures. Accumulating evidence indicates that synovial tissue, synovial fluid, and articular cartilage harbor a functionally active joint-local renin-angiotensin system that operates partially autonomously from the systemic RAS circulation and is implicated in the pathogenesis of both arthritis (RA) and osteoarthritis (OA). This narrative review integrates human, animal, and in vitro evidence to examine the dual-axis organization of the joint RAS, comprising a pathogenic angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II)/ Angiotensin II type 1 receptor (AT1R) axis and a counter-regulatory ACE2/Angiotensin-(1-7) (Ang-(1-7))/Mas receptor-Mas related G protein-coupled receptor D (Mas-MrgD) axis, and to explore how imbalance between these pathways may differentially influence inflammatory and degenerative joint diseases. In RA, experimental and translational studies suggest that enhanced activity of the classical axis within synovial tissue is associated with synovial inflammation, fibroblast-like synoviocyte survival, angiogenesis, and bone erosion through pathways involving nuclear factor kappa B (NF-kB), mitogen-activated protein kinase (MAPK), and receptor activator of nuclear factor kB ligand (RANKL)/Wingless-related integration site (Wnt) signaling pathway. In OA, available data indicate that chondrocyte expression of AT1R/Angiotensin II type 2 receptor (AT2R), together with cytokine-induced receptor upregulation, may sensitize cartilage to Ang II-mediated effects, contributing to matrix metalloproteinase-13 (MMP-13)-mediated matrix degradation and activation of interleukin-6 (IL-6)/janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling. Genetic studies support disease-specific patterns, with the ACE insertion/deletion polymorphism showing a more consistent association with RA susceptibility than with knee OA, although findings vary across populations and do not consistently correlate with disease severity. From a therapeutic perspective, modulation of the joint-local RAS is currently supported mainly by preclinical evidence. Experimental models suggest that classical RAS inhibitors and emerging strategies targeting the protective axis-such as putative ACE2 activators, AT2R agonists, and bone-targeted peptide delivery can influence inflammatory and structural pathways within the joint, while direct clinical evidence remains limited. Overall, current data support the biological relevance of a local joint RAS in arthritis pathophysiology and highlight key gaps between experimental findings and clinical translation.

Dual Inhibition of the Renin-Angiotensin-Aldosterone System and Sodium-Glucose Cotransporter-2: Mechanistic and Clinical Evidence for Cardiorenal Protection.

Reem F M Aazar, Rayan Arzouni, Persoulla A Nicolaou

Overactivation of the renin-angiotensin-aldosterone system (RAAS) promotes haemodynamic overload, inflammation, and fibrosis in the heart and kidneys. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a cornerstone therapy in cardiorenal protection. Emerging data indicate that adding SGLT2 inhibitors to angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, or angiotensin receptor-neprilysin inhibitors confers additional cardiorenal protection, yet their mechanistic basis and optimal clinical use in cardiovascular (CV) disease remain unclear. This review will integrate pre-clinical and clinical evidence on dual RAAS/SGLT2 modulation in CV disease, providing mechanistic insight into dual therapy. The review will finally outline priorities for future translational and outcome studies. Clinically, adding SGLT2 inhibitors to RAAS-based therapy reduces heart failure hospitalizations and slows kidney disease progression without new safety liabilities in type 2 diabetes, heart failure, and chronic kidney disease. Mechanistically, SGLT2 inhibition restores tubuloglomerular feedback and constricts the afferent arteriole; RAAS blockade dilates the efferent arteriole, and together, they lower intraglomerular pressure. Both classes also reduce oxidative stress, inflammatory signalling, and pro-fibrotic pathways, with SGLT2 inhibitors in several settings shifting RAAS balance toward the protective ACE2/angiotensin-(1-7)/Mas receptor axis. Key gaps include the scarcity of adequately powered trials designed to test combination therapy versus either component alone, limited evidence on timing and sequencing, incomplete characterization in high-risk groups, and mechanistic insight limited by study design in animal and cell models. Collectively, current data support layering SGLT2 inhibitors onto RAAS-based therapy, while definitive evidence from dedicated clinical trials is awaited.

Dual role of ACE2 in regulating inflammation triggered by Omicron S1 and other SARS-CoV-2 Spike variants.

Annamaria Pedoto, Juan M Lozano-Gil, María Ocaña-Esparza +5 more

Since the emergence of SARS-CoV-2 in late 2019, substantial efforts have been made to understand its mechanisms of pathogenicity. Although angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for viral entry, the complexity of the host immune response to different Spike protein conformations and variants remains poorly understood. Using zebrafish larvae as an in vivo model, we show that the monomeric S1 domain of the Omicron variant triggers a potent proinflammatory response characterized by elevated Nfkb activity and increased expression of key cytokines, despite reduced recruitment and expansion of neutrophils and macrophages. Notably, monomeric S1 Omicron also promotes neutrophil cell death, suggesting an alternative mechanism of immune modulation. In contrast, the trimeric form of the Spike protein fails to induce significant inflammation or emergency hematopoiesis, likely due to its efficient neutralization by endogenous Ace2. Our results revealed that both zebrafish and human ACE2 exert a dual anti-inflammatory role: indirectly through the production of angiotensin-(1-7), and directly by binding and neutralizing the trimeric Spike. These results provide new insights into variant-specific immune responses and the multifaceted role of ACE2 in modulating SARS-CoV-2-induced cytokine storm syndrome.

Telmisartan reduces systemic inflammation and alters the renin-angiotensin system in mild COVID-19.

Angela Lu, Melissa Agsalda-Garcia, Weiyuan Hu +14 more

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a respiratory viral infection that disrupts renin angiotensin system (RAS) peptide metabolism by downregulating angiotensin converting enzyme-II (ACE2), leading to accumulation of pro-inflammatory angiotensin II (AngII). We posit that angiotensin receptor blockers (ARBs) like telmisartan (TEM) can activate the pro-resolving arm of RAS (MasR/ACE2/Ang1-7), reducing lung inflammation in COVID-19 patients. In this randomized, double-blinded, placebo-controlled pilot clinical trial, outpatient SARS-CoV-2-infected study participants received either 40 mg TEM or placebo once daily. Plasma inflammatory biomarker levels revealed a reduction in global systemic inflammation with TEM treatment, corresponding with an increase in MasR. We corroborated these clinical findings with in vitro analysis. A549-ACE2 lung epithelial cells treated with TEM showed increased ACE2 and MasR, as well as decreased angiotensin II receptor type I (AT1R) and angiotensin II receptor type II (AT2R) expression levels. Additionally, AngII peptide levels decreased, while Ang(1-9) and Ang(1-7) increased. TEM treatment at physiologically achievable concentration reduced SARS-CoV-2 viral load. Taken collectively, these results show TEM mediated activation of the Ang(1-7)/MasR/ACE2 pro-resolving arm of RAS, which activates anti-inflammatory events that reduce global inflammation. These findings support the use of ARBs like TEM in mitigating COVID-19 driven alterations in RAS.

Exogenous hydrogen sulfide inhibits the progression of vascular dysfunction and hypertension mediated by the renin-angiotensin system in chronic kidney disease.

Jorge A Tapia-Martínez, Diana L Silva-Velasco, Jesus H Beltran-Ornelas +3 more

Chronic kidney disease (CKD) overactivates the renin-angiotensin system (RAS), causing vascular dysfunction and hypertension. Additionally, hydrogen sulfide (H2S) is a gasotransmitter that modulates the cardiovascular system by attenuating the RAS. Therefore, this study aimed to investigate the effects of chronic administration of sodium hydrosulfide (NaHS, an exogenous H2S donor) on RAS-mediated vascular responses, oxidative stress, and progression of hypertension in rats with CKD. Thirty-two normotensive male Wistar rats were divided into four groups (n = 8): 1) sham + vehicle (1 mL/kg/d, 100 mM of phosphate buffer, PBS), 2) sham + NaHS (5.6 mg/kg/d), 3) CKD induced by 5/6 nephrectomy + vehicle, and 4) CKD + NaHS. One week after surgery, pharmacological treatments began and were administered intraperitoneally daily for six weeks. Hemodynamic variables, renal function, and H2S serum levels were assessed. Additionally, H2S formation, oxidative stress, and the expression of AT1, AT2, Mas receptors, and H2S-synthesizing enzymes, along with vascular responses to angiotensin (1-7), angiotensin II and H2S were assessed in the thoracic aorta. CKD impairs: 1) RAS-mediated vascular responses; 2) downregulates Mas receptor expression; 3) upregulates AT1 and AT2 receptor expression; 4) increases H2S-mediated vascular response, 5) decreases H2S levels, tissue production of H2S and the expression of the producing enzymes; and 6) induces oxidative stress. Interestingly, NaHS treatment prevented CKD-induced impairments. In conclusion, NaHS administration protects against RAS-mediated vascular dysfunction and progression of hypertension by preventing alterations in AT1, AT2, Mas receptors, H2S-synthesizing enzymes, and oxidative stress.

Amylin and the renin-angiotensin system: risk or opportunity in amylin-based therapy?

Marcel H A Muskiet, Massimo Nardone, Patrick C N Rensen +2 more

We hypothesise that amylin receptor agonists (eg, pramlintide) and dual amylin and calcitonin-receptor agonists (eg, cagrilintide), which are emerging treatments for obesity and type 2 diabetes, can activate the renin-angiotensin system (RAS) and potentially undermine the cardiorenal benefits of these therapies. Paradoxically, new-generation amylin-based therapies, such as CagriSema, showed substantial blood pressure reductions in phase 3 trials. Beyond amylin's weight loss-mediated effects, we hypothesise that concurrent use of RAS inhibitors (angiotensin-converting enzyme [ACE] inhibitors or angiotensin-receptor blockers) redirects amylin-induced RAS activation towards the protective alternative RAS pathway, which is characterised by vasodilatory, anti-inflammatory, and antiproliferative effects via Mas receptors, potentially explaining part of their therapeutic benefit and cardioprotective and renoprotective potential. To test this, we propose: (1) preclinical studies investigating amylin-RAS interactions with or without RAS blockade; (2) post-hoc analyses of phase 2/3 trials stratified by RAS inhibitor use; (3) biomarker studies monitoring renin, aldosterone, angiotensin-(1-7), and ACE2; and (4) mechanistic human studies prospectively assessing cardiovascular-kidney metabolic effects by RAS inhibitor status. These suggestions aim to determine whether RAS inhibition enhances the overall efficacy of amylin-based therapies, and whether RAS blockers should be strongly recommended in patients receiving them.

Persistent renin-angiotensin system and inflammatory dysregulation following COVID-19 impairs ischemic stroke recovery.

Amy May Lin Quek, Ooiean Teng, Ju-Hea Park +3 more

Previous studies indicate that stroke recovery is worse in patients with prior COVID-19, suggesting persistent biological perturbations. We investigated lingering renin-angiotensin system (RAS) and inflammatory alterations after COVID-19 to uncover mechanisms driving impaired ischemic stroke recovery. We conducted a prospective observational cohort study comparing clinical and molecular profiles of ischemic stroke patients with and without recent COVID-19 infection to age-matched healthy controls. Plasma angiotensin-(1-7), angiotensin II, and soluble ACE2 were quantified, high-throughput proteomic profiling was performed using the Olink® Explore platform, and RNA sequencing was conducted to identify molecular mechanisms related to COVID-19-associated stroke and stroke outcomes (90-day modified Rankin Scale (mRS)). A total of 189 participants (38 COVID-19-associated stroke, 77 non-COVID-19 stroke, and 74 healthy controls) were enrolled. COVID-19-associated stroke patients exhibited significantly higher proportions of cryptogenic strokes (21.1 % vs 10.4 %), earlier hospital presentation (mean 185 vs 310 min), greater use of endovascular thrombectomy (97.4 % vs. 52.6 %), yet poorer functional outcomes (mRS ≥3) at 3 months (73 % vs. 47 %, all p < 0.05). Both stroke groups showed elevated angiotensin-(1-7) levels compared to controls, but angiotensin II levels were notably higher only in non-COVID-19 stroke patients. Proteomic analysis revealed sustained elevation of interferon-gamma (IFN-γ) signaling in COVID-19-associated stroke patients. Reduced AKT3 levels emerged as a significant predictor of poor outcomes, independent of renin-angiotensin biomarkers (adjusted OR 0.40; 95 % CI 0.16-0.94). Stroke patients with low AKT3 levels and poor outcomes exhibited significant upregulation of ribosomal proteins (RPS15, RPS4X, RPS7, RPS18, RPSA, RPS27A, RPS13, RPS23), reflecting heightened translational stress. Persistent RAS and inflammatory dysregulation following COVID-19 may contribute to worse stroke recovery. Future studies should validate and investigate the therapeutic implications of these findings.

Fenofibrate as a Modulator of the Renin-Angiotensin System in Su/Hx-Induced Pulmonary Arterial Hypertension.

Karla M Rada-Pascual, Alejandra M Zúniga-Muñoz, Yamnia Q Alvarez-Alvarez +11 more

We evaluated the effects of fenofibrate (FF) in a SU5416/hypoxia model of pulmonary arterial hypertension (PAH) with a specific focus on its influence on the renin-angiotensin system (RAS). We assessed right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (mPAP), medial pulmonary artery wall thickening, right ventricular (RV) hypertrophy, systolic pulmonary artery pressure (SPAP), pulmonary artery effective elastance (PAEa), RV diastolic pressure (RVDP), RV developed pressure (RVDevP), right ventricular-pulmonary arterial coupling index (RVPAC), RV dp/dt max and dp/dt min. Levels of angiotensin II, angiotensin (1-7), angiotensin-converting enzyme 2 (ACE2), Bmpr2, Smad5 and nitrite (NO2-) and nitrate (NO3-) in the lung and RV were evaluated. The expression of AT1R, MAS receptors, and ACE2 in lung tissue was assessed. FF prevented the increase in RVSP, mPAP, RV hypertrophy, reduced pulmonary arterioles remodeling, and attenuated the rise in SPAP, mPAP, and PAEa. In the RV, it reduced RVDevP and prevented the decrease in dp/dt min, without affecting RVDP. RVPAC showed partial improvement. In lung tissue, FF decreased angiotensin II levels, the Ang II/Ang-(1-7) ratio, and reduced angiotensin II receptor type 1 (AT1R) expression, while preserving the receptor for the angiotensin-(1-7) (MAS) and ACE2. FF tended to restore Bmpr2/Smad5 expression. NO2- levels were preserved and tended to preserve (NO3-) levels. In the RV, Ang-(1-7) increased, ACE2 was preserved, and NO2- and NO3 levels were maintained. FF exerts protective effects in Su/Hx-induced PAH.

Dapagliflozin monotherapy and combination therapy with telmisartan ameliorate pregabalin-induced heart failure in rats.

Zeinab M Awwad, Shimaa A Mahmoud, Shaimaa M Kh Abdelaziz +1 more

Heart failure (HF) associated with pregabalin (PRG) administration hampers its use in epilepsy, neuropathy and anxiety. Overactivation of cardiac renin angiotensin system (RAS) contributes to PRG-induced HF. The goal of the current study was to investigate the possible cardioprotective effects of dapagliflozin (DAPA), a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, compared with that of the combination therapy of DAPA and telmisartan (Tel) in attenuating PRG-associated HF by examining echocardiographic, morphometric and histopathological parameters. Moreover, to explore the possible beneficial impacts of DAPA and the combination therapy in guarding against PRG-induced myocardial alterations of angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7) levels, in addition to angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), angiotensin II type 1 (AT1) receptor and Mas receptor (MAS1) levels. Results demonstrated that PRG use lead to echocardiographic, morphometric and histopathological detrimental changes and profoundly elevated ACE, Ang II and AT1 cardiac levels, while reduced cardiac ACE2, Ang 1-7 and MAS1 levels. Concurrent administration of either DAPA monotherapy or the combination therapy counteracted the deleterious echocardiographic, morphometric and histopathological alterations associated with PRG administration and showed notable protection against PRG-associated HF through activation of ACE2/Ang 1-7/MAS1 axis and suppression of ACE/Ang II/AT1 axis. However, the combination therapy group showed more cardioprotective effects than that of DAPA-treated group. The current findings provided the first evidence for the potential protective effects of DAPA monotherapy and combination therapy with Tel against PRG-induced altered balance between the two RAS axes.

Publisher Correction: Investigation of the relationship between COVID-19 disease and semen parameters in idiopathic male infertility patients.

M B Can Balcı, N Can Çilesiz

Eur Rev Med Pharmacol Sci 2023; 27 (1): 378-383-DOI: 10.26355/eurrev_202301_30891-PMID: 36647886, published online on January 13, 2023. This erratum addresses errors in the reference list of the published PDF version. Due to an internal error during layout finalization, incorrect references from another article were inadvertently inserted into the final PDF. The error was not detected by the authors prior to publication, and the PDF file was approved for publication. The corrected list of references is provided below: 1.         Chen J, Jiang Q, Xia X, Liu K, Yu Z, Tao W, Gong W, Han JJ. Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell 2020; 19: e13168. 2.         Atlas SA. The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J Manag Care Pharm 2007; 13: 9-20. 3.         Stanley KE, Thomas E, Leaver M, Wells D. Coronavirus disease-19 and fertility: viral host entry protein expression in male and female reproductive tissues. Fertil Steril 2020; 114: 33-43. 4.         Younis JS, Abassi Z, Skorecki K. Is there an impact of the COVID-19 pandemic on male fertility? The ACE2 connection. Am J Physiol Endocrinol Metab 2020; 318: E878-E880. 5.         Reis AB, Araújo FC, Pereira VM, Dos Reis AM, Santos RA, Reis FM. Angiotensin (1-7) and its receptor Mas are expressed in the human testis: implications for male infertility. J Mol Histol 2010; 41: 75-80. 6.         Tiwari S, Kc N, Thapa S, Ghimire A, Bijukchhe S, Sah GS, Isnuwardana R. Semen parameters in men recovered from COVID-19: a systematic review and meta-analysis. Middle East Fertil Soc J 2021; 26: 44-53. 7.         Boitrelle F, Shah R, Saleh R, Henkel R, Kandil H, Chung E, Vogiatzi P, Zini A, Arafa M, Agarwal A. The Sixth Edition of the WHO Manual for Human Semen Analysis: A Critical Review and SWOT Analysis. Life (Basel) 2021; 11: 1368. 8.         Cocuzza M, Agarwal A. Nonsurgical treatment of male infertility: spesific and empiric therapy. Biologics 2007; 1: 259-269. 9.         Twigg JP, Irvine DS, Aitken RJ. Oxidative damage to DNA in human spermatozoa does not preclude pronucleus formation at intracytoplasmic sperm injection. Hum Reprod 1998; 13: 1864-1871. 10.          Tremellen K. Oxidative stress and male infertility-a clinical perspective. Hum Reprod Update 2008; 14: 243-258. 11.          Wang Z, Xu X. scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in Spermatogonia, Leydig and sertoli Cells. Cells 2020; 9: 920. 12.          Dejucq N, Jégou B. Viruses in the mammalian male genital tract and their effects on the reproductive system. Microbiol Mol Biol Rev 2001; 65: 208-231. 13.          Heller CG, Clermont Y. Spermatogenesis in man: an estimate of its duration. Science 1963; 140: 184-186. 14.          Pan F, Xiao X, Guo J, Song Y, Li H, Patel DP, Spivak AM, Alukal JP, Zhang X, Xiong C, Li PS, Hotaling JM. No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil Steril 2020; 113: 1135-1139. 15.          Bian XW. COVID-19 Pathology Team. Autopsy of COVID-19 patients in China. Natl Sci Rev 2020; 7: 1414-1418. 16.          Yang M, Chen S, Huang B, Zhong JM, Su H, Chen YJ, Cao Q, Ma L, He J, Li XF, Li X, Zhou JJ, Fan J, Luo DJ, Chang XN, Arkun K, Zhou M, Nie X. Pathological Findings in the Testes of COVID-19 Patients: Clinical Implications. Eur Urol Focus 2020; 6: 1124-1129. 17.          Paoli D, Pallotti F, Turriziani O, Mazzuti L, Antonelli G, Lenzi A, Lombardo F. SARS-CoV-2 presence in seminal fluid: Myth or reality. Andrology 2021; 9: 23-26. 18.          Guo TH, Sang MY, Bai S, Ma H, Wan YY, Jiang XH, Zhang YW, Xu B, Chen H, Zheng XY, Luo SH, Xie XF, Gong CJ, Weng JP, Shi QH. Semen parameters in men recovered from COVID-19. Asian J Androl 2021; 23: 479-483. 19.          Hu B, Liu K, Ruan Y, Wei X, Wu Y, Feng H, Deng Z, Liu J, Wang T. Evaluation of mid- and long-term impact of COVID-19 on male fertility through evaluating semen parameters. Transl Androl Urol 2022; 11: 159-167. 20.          Ruan Y, Hu B, Liu Z, Liu K, Jiang H, Li H, Li R, Luan Y, Liu X, Yu G, Xu S, Yuan X, Wang S, Yang W, Ye Z, Liu J, Wang T. No detection of SARS-CoV-2 from urine, expressed prostatic secretions, and semen in 74 recovered COVID-19 male patients: A perspective and urogenital evaluation. Andrology 2021; 9: 99-106. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/30891.

Is the renin-angiotensin system a friend or foe in neurological diseases? Unveiling its role and therapeutic potential.

Pratyush Porel, Garry Hunjan, Shamsher Singh +1 more

The renin-angiotensin system (RAS), an important regulator of body fluid and cardiovascular homeostasis, is gradually implicated in the pathogenesis of neurological diseases due to its dysregulation. In addition to their traditional functions, components of the RAS, especially angiotensin-II (Ang-II), enhance neuroinflammation, oxidative stress, and neuronal injury. Ang-II exacerbates blood-brain barrier (BBB) disruption, promotes glial activation, and contributes to neurodegeneration via the Angiotensin type 1 (AT1) receptor (AT1R) and causes neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), epilepsy, depression, and anxiety. The angiotensin (1-7) axis mediated by the Mas receptor appears to be neuroprotective, however, as it reverses the negative effects of Ang-II. In experimental models and clinical trials, blocking RAS specifically by angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) has demonstrated promise in reducing neuroinflammation and neuronal damage, especially in stroke and neurodegenerative diseases. In the current era of research, neuropharmacologists have new optimism due to emerging evidence of the promising potential of RAS-modulating drugs, such as ARBs and ACEIs, in the treatment of various neurological diseases. Since RAS imbalance causes neuroinflammation, neuronal damage, and cognitive decline in conditions including AD, PD, and MS, these drugs may offer a new treatment approach. In the current era of neuropharmacology, this technique is novel since it enables more targeted therapies to address the root causes of neurodegeneration. This review explores the molecular pathways of RAS dysregulation in various neurological diseases, highlighting its therapeutic potential and paving the way for future treatment strategies.

β-Caryophyllene's potential modulation of the renin-angiotensin system: Implications for anosmia and neuroinflammation in the olfactory circuitry.

Hugo Alejandro Espinoza-Gutiérrez, Sofía Cecilia López-Salido, Mario Eduardo Flores-Soto +3 more

The sense of smell perceives odorants via the olfactory circuitry. Sense of smell is essential for multiple species, while its loss in humans (Anosmia) has been described in COVID-19, Parkinson's and Alzheimer's diseases, where neuroinflammation is a common denominator. Olfactory circuitry is proximal to the respiratory tract, therefore, is susceptible to foreign particles intromission that trigger neuroinflammation. The brain Renin-Angiotensin System (RAS) influence neuroinflammation through its counter-regulatory axes: The pro-inflammatory Renin/(Pro)Renin Receptor ((P)RR) axis and the anti-inflammatory Angiotensin-Converting Enzyme 2 (ACE2)/Angiotensin-(1-7) (Ang-(1-7))/Mas Receptor (MasR) axis. Certain phytochemicals with angiotensinergic activity may improve neuroinflammation. Among these, β-Caryophyllene, stands out for its bicyclic sesquiterpenoid structure and its activity toward multiple targets, including the Cannabinoid Receptor 2 and the peripheral ACE2/Ang-(1-7)/MasR axis. It is still unknown whether β-Caryophyllene affects the brain RAS, especially in vulnerable regions to neuroinflammation, like the olfactory circuitry. This study aims to explore the angiotensinergic effect of β-Caryophyllene on anosmia and the neuroinflammation of the olfactory circuitry. Male BALB/c mice were intranasally administered with lipopolysaccharide and orally treated with β-Caryophyllene for seven days. Multiple parameters concerning RAS, olfaction, neuroinflammation, cell death and stress were evaluated. Results demonstrate that β-Caryophyllene improved anosmia, increased ACE2 and Ang-(1-7) levels, reduced pro-inflammatory cytokines as well as reduced corticosterone levels and cell death. Molecular docking showed favorable interactions between β-Caryophyllene and ACE2. Therefore, β-Caryophyllene could be useful against anosmia and neuroinflammation due to the possible regulation of the RAS.

ACE2/Ang(1-7)/MasR axis exerts protective effects on lung ischemia/reperfusion injury via NF-κB-dependent mitochondrial adaptation and epithelial cell pyroptosis.

Yin Chen, Liang Guo, Juan Shen +2 more

Mitochondrial dysfunction and pyroptosis of epithelial cells are main contributors to the pathological process of lung ischemia/reperfusion (I/R) injury. Angiotensin-converting enzyme 2 (ACE2) has been implicated in suppressing lung injury. Accordingly, this study investigated whether ACE2 could attenuate mitochondrial dysfunction and pyroptosis after lung I/R injury.

The Renin-Angiotensin-Aldosterone System (RAAS): Beyond Cardiovascular Regulation.

Agnese Valentini, Romy M Heilmann, Anna Kühne +3 more

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in regulating cardiovascular function, fluid balance, and blood pressure. Recent research has revealed the RAAS's influence extends beyond cardiovascular physiology, encompassing key roles in inflammation, fibrosis, immune regulation, cancer progression, and organ-specific disease mechanisms. This review provides a comprehensive overview of classical and alternative RAAS pathways, focusing on the dual roles of angiotensin II (Ang II) and angiotensin-(1-7) (Ang 1-7), mediated through AT1R, AT2R, MasR, and MrgD receptors. We discuss molecular signaling cascades, including mitochondrial, nuclear, and caveolae-mediated mechanisms, and explore the impact of RAAS modulation on hepatic fibrosis, vascular remodeling, and autoimmune inflammation. Genetic models and emerging pharmacologic strategies illustrate tissue-specific RAAS actions, emphasizing the therapeutic potential of enhancing the ACE2/Ang 1-7/Mas axis while inhibiting the deleterious ACE/Ang II/AT1R signaling. Furthermore, we highlight implications for veterinary medicine, particularly in canine chronic inflammatory enteropathies, where RAAS dysfunction may contribute to treatment resistance. Understanding RAAS complexity and inter-receptor crosstalk is essential for developing new therapeutic strategies targeting cardiovascular, hepatic, and inflammatory diseases in both human and veterinary contexts.

Physiopathology of the Brain Renin-Angiotensin System.

Cristina Cueto-Ureña, María Jesús Ramírez-Expósito, María Pilar Carrera-González +1 more

The renin-angiotensin system (RAS) has evolved from being considered solely a peripheral endocrine system for cardiovascular control to being recognized as a complex molecular network with important functions in the central nervous system (CNS) and peripheral nervous system (PNS). Here we examine the organization, mechanisms of action, and clinical implications of cerebral RAS in physiological conditions and in various neurological pathologies. The cerebral RAS operates autonomously, synthesizing its main components locally due to restrictions imposed by the blood-brain barrier. The key elements of the system are (pro)renin; (pro)renin receptor (PRR); angiotensinogen; angiotensin-converting enzyme types 1 and 2 (ACE1 and ACE2); angiotensin I (AngI), angiotensin II (AngII), angiotensin III (AngIII), angiotensin IV (AngIV), angiotensin A (AngA), and angiotensin 1-7 (Ang(1-7)) peptides; RAS-regulating aminopeptidases; and AT1 (AT1R), AT2 (AT2R), AT4 (AT4R/IRAP), and Mas (MasR) receptors. More recently, alamandine and its MrgD receptor have been included. They are distributed in specific brain regions such as the hypothalamus, hippocampus, cerebral cortex, and brainstem. The system is organized into two opposing axes: the classical axis (renin/ACE1/AngII/AT1R) with vasoconstrictive, proinflammatory, and prooxidative effects, and the alternative axes AngII/AT2R, AngIV/AT4R/IRAP, ACE2/Ang(1-7)/MasR and alamandine/MrgD receptor, with vasodilatory, anti-inflammatory, and neuroprotective properties. This functional duality allows us to understand its role in neurological physiopathology. RAS dysregulation is implicated in multiple neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and neuropsychiatric disorders such as depression and anxiety. In brain aging, an imbalance toward hyperactivation of the renin/ACE1/AngII/AT1R axis is observed, contributing to cognitive impairment and neuroinflammation. Epidemiological studies and clinical trials have shown that pharmacological modulation of the RAS using ACE inhibitors (ACEIs) and AT1R antagonists (ARA-II) not only controls blood pressure but also offers neuroprotective benefits, reducing the incidence of cognitive decline and dementia. These effects are attributed to direct mechanisms on the CNS, including reduction of oxidative stress, decreased neuroinflammation, and improved cerebral blood flow.

The renin-angiotensin system in healthy human platelets: expressed but inactive.

François Panosetti, François M Cuenot, Damian S Saint Auguste +11 more

Platelets play a crucial role in arterial thrombus formation, offering potential for new antiplatelet therapies with reduced bleeding risk. Here, we investigated the role of the renin-angiotensin system (RAS) in human platelets and explored its potential link to COVID-19 coagulopathy. Experiments were performed ex vivo on healthy human platelets. The expression of RAS receptors (Mas, MrgD, ACE, ACE2, AT1 and AT2) was evaluated using western blot and immunofluorescence. Platelets were incubated in vitro with either Captopril or different RAS peptides including Alamandine, Angiotensin-I, Angiotensin-II, Angiotensin-(1-7), and Angiotensin-(1-9). Platelet adhesion was measured by spectrophotometry using BCECF fluorescence. Platelet activation and aggregation were analyzed using aggregometry after stimulation with extracellular matrix proteins. ACE and ACE2 activity were assessed using Fluorescent Peptides (FPS). We demonstrated that healthy human platelets express all the tested RAS receptors. However, RAS peptides did not modulate platelet adhesion or aggregation despite a wide range of concentrations tested. ACE activity was detected in platelet lysates, but it was not inhibited by Captopril, while ACE2 activity was undetectable. Our findings suggest that while RAS receptors are expressed in platelets, RAS peptides do not impact platelet function, at least in our experimental setting. COVID-19 coagulopathy may occur independently of the RAS.

ACE2/Angiotensin-(1-7)/Mas and the brain.

Maria José Campagnole-Santos, Marco Antônio Peliky Fontes, Thiago Verano-Braga +3 more

It is well known that the renin-angiotensin system (RAS) plays a key role in regulating blood pressure and hydroelectrolyte balance. In addition to angiotensin (Ang) II, Ang-(1-7) has emerged as an important component of this system. Here we review evidence regarding the presence and actions of ACE2/Ang-(1-7)/Mas receptor pathway within the central nervous system, where the RAS possesses a crucial role in controlling cardiovascular, metabolic and stress-coping behavior functions. The involvement of this non-canonical RAS pathway in the brain mechanisms related to hypertension will also be discussed.

Role of G-protein-coupled receptor kinase 4 on the dysfunction of renal Mas receptor in hypertension.

Lin Chen, Jiayao Chen, Jindong Wan +5 more

The angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor axis plays an important role in the regulation of blood pressure. G protein-coupled receptor kinase 4 (GRK4) has attracted more attentions by modulating G protein-coupled receptors and blood pressure. However, it remains unknown whether renal Mas receptor is regulated by GRK4 and its role in the pathogenesis of hypertension. Compared with Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs) exhibited impaired Mas receptor-mediated diuresis and natriuresis, which was accompanied with increased phosphorylation levels of Mas receptors. Similarly, the phosphorylation of renal Mas receptor was increased and its-induced renal effects were decreased in human (h) GRK4γ 142V transgenic mice relative to wild-type littermates. There was a colocalization and a direct interaction of renal Mas receptor and GRK4, which were increased in SHRs and confirmed by rigid protein-protein docking. In vitro studies found that treatment with the Mas receptor agonist AVE0991 inhibited Na+-K+-ATPase activity in WKY renal proximal tubule (RPT) cells, which was failed in SHR cells. GRK4 silencing decreased the phosphorylation of Mas receptor and improved the impaired Mas receptor-mediated inhibition of Na+-K+-ATPase activity in SHR RPT cells. Further study showed that ultrasound-targeted microbubble destruction-targeted renal GRK4 depletion decreased Mas receptor phosphorylation and improved its-induced diuresis and natriuresis in SHRs. These suggest that GRK4 contributes to increased renal Mas receptor phosphorylation and dysfunction in hypertension, indicating that targeting GRK4 may be a viable therapeutic approach for hypertension.

Assessment of Selected Biochemical Parameters of the Renin-Angiotensin-Aldosterone System in Repeat Convalescent Plasma Donors in the Context of Long-Term Changes Following SARS-CoV-2 Infection.

Marta Stanek, Dorota Diakowska, Krzysztof Kaliszewski +1 more

Background: SARS-CoV-2 infection has been associated with long-term health consequences, including dysregulation of the renin-angiotensin-aldosterone system (RAAS). This study aimed to evaluate long-term changes in selected RAAS-related biochemical parameters in repeat convalescent plasma donors, focusing on enzymes and peptides involved in vascular regulation and inflammation. Methods: Thirty repeat convalescent plasma donors were enrolled, each providing four serum samples at defined time points post-infection. Samples were collected during Period 1 (≤60 days), Period 2 (61-90 days), Period 3 (91-120 days), and Period 4 (>120 days) after confirmed SARS-CoV-2 infection. The analyzed parameters included angiotensin I (Ang I), angiotensin II (Ang II), angiotensin 1-7 (Ang 1-7), angiotensin 1-9 (Ang 1-9), ACE, ACE2, ADAM10, and ADAM17. Concentrations were determined using ELISA assays. The control group consisted of pre-pandemic serum samples from healthy individuals. Results: An initial post-infection increase was observed in most parameters, particularly in Period 1. Over time, levels of several markers declined, yet Ang 1-7 and Ang 1-9 remained elevated compared to controls even beyond 120 days. Significant correlations (p < 0.05) were found between ADAM10, ADAM17, and angiotensin peptides, suggesting prolonged RAAS modulation. Metalloproteinases were notably elevated early after infection, potentially contributing to inflammatory and cardiovascular responses. Conclusions: The findings indicate a transient but measurable biochemical response of the RAAS following SARS-CoV-2 infection, with most parameters normalizing after 120 days. However, the sustained elevation of certain markers suggests a potential long-term impact on vascular homeostasis, warranting further investigation.

Naturally Occurring Angiotensin Peptides Enhance the SARS-CoV-2 Spike Protein Binding to Its Receptors.

Katelin X Oliveira, Fariha E Bablu, Emily S Gonzales +2 more

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for Coronavirus Disease 2019 (COVID-19), utilizes its spike protein to infect host cells. In addition to angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1), AXL acts as a spike protein receptor and mediates infection, especially in respiratory cells with low ACE2 expression. Angiotensin II (1-8) can be cleaved into shorter peptides within the biological system. Antibody-based binding assays showed that angiotensin II causes a two-fold increase in the binding between the spike protein and AXL, but not ACE2 or NRP1. While a longer peptide, angiotensin I (1-10), did not affect the spike-AXL binding, shorter lengths of angiotensin peptides exhibited enhancing effects. The C-terminal deletions of angiotensin II to angiotensin (1-7) or angiotensin (1-6) resulted in peptides with enhanced activity toward spike-AXL binding with a similar capacity as angiotensin II. In contrast, the N-terminal deletions of angiotensin II to angiotensin III (2-8) or angiotensin IV (3-8) as well as the N-terminal deletions of angiotensin (1-7) to angiotensin (2-7) or angiotensin (5-7) produced peptides with a more potent ability to enhance spike-AXL binding (2.7-fold increase with angiotensin IV). When valine was substituted for tyrosine at position 4 in angiotensin II or when tyrosine at position 4 was phosphorylated, spike-AXL binding was increased, suggesting that modifications to tyrosine trigger enhancement. Angiotensin IV also enhances spike protein binding to ACE2 and NRP1. Thus, angiotensin peptides may contribute to COVID-19 pathogenesis by enhancing spike protein binding and thus serve as therapeutic targets.

Role of the renin-angiotensin pathway in epilepsy: a strategy for its management by drug repurposing.

Rakesh Bagle, Shubham Teli, Bhushan Khombare +1 more

Epilepsy is a neurological disorder characterised by aberrant synchronised neuronal activity in the brain and affects millions of people globally. The renin-angiotensin system (RAS) has been implicated in epilepsy pathophysiology, with angiotensin receptors playing pivotal role in seizure modulation and neuroprotection. This review explores the angiotensin-epilepsy axis, and elaborates upon the role of angiotensin receptors (AT-1, AT-2, AT-4, and Mas) in the CNS. AT-1 receptor stimulation is related to neuroinflammation, oxidative stress, and propagation of seizures, whereas their blockade by angiotensin receptor blockers (ARBs) demonstrated anticonvulsant and neuroprotective effects in preclinical model. AT-2 receptor activation down-regulates pro-inflammatory cytokines & protects the blood-brain barrier and induces neuronal survival and differentiation. They also interact with the AT-4 receptor identified as insulin-regulated amino peptidase (IRAP), a receptor that is implicated in its neuroinflammatory modulation, oxidative stress, and excitotoxicity. Against this background, the Mas receptor was recognized as the receptor for angiotensin-(1-7), leading to vasodilator, anti-inflammatory and anti-oxidant effects that oppose angiotensin II actions. This intricate interplay between these receptors and ligands accompanies the dynamic regulation of neurotransmitters, neuroinflammation, and neuroprotection in epileptic seizures. The role of the RAS in epilepsy may present new therapeutic targets in addressing this devastating disorder, especially in patients with coexisting cardiovascular illnesses.

Advancing antihypertensive drug development.

Fay Pu, Yanrong Liu, Fozia Zahir Ahmed +3 more

Hypertension affects more than a billion individuals worldwide and remains a major cause of cardiovascular morbidity and mortality. Despite advances in therapies, optimal blood pressure control remains elusive for many patients because of treatment resistance, adverse effects, and adherence challenges. This review highlights innovative approaches in hypertension management. Aldosterone synthase inhibitors (ASIs) and non-steroidal mineralocorticoid receptor antagonists improve blood pressure control and offer cardiorenal benefits while reducing adverse effects including hyperkalaemia. Endothelin receptor antagonists show promise in resistant hypertension by addressing vasoconstrictive pathways. RNA-based therapies, like zilebesiran, provide a novel approach to suppress angiotensinogen, offering durable antihypertensive effects with less frequent dosing. Additional advances include AT2 receptor agonists, ACE2/Angiotensin-(1-7)/MAS receptor activators and NAD+ boosting compounds, which target key mechanisms of vascular dysfunction and ageing-related hypertension. Gut microbiome-targeted therapies and fixed-dose combination pills are also discussed for their potential to enhance blood pressure control and patient adherence. These emerging therapies not only aim to lower blood pressure but also address underlying pathophysiological mechanisms, offering a precision-focussed approach to treatment. By critically analysing these developments, this review provides insights into how novel strategies can overcome existing challenges in hypertension management, reduce the global disease burden and improve patient outcomes.

Effects of Hormone Replacement Treatment with Estrogen and Progestins on the Vascular Renin-Angiotensin System of Ovariectomized Rats.

Laís Almeida Menezes, Patrick Wander Endlich, Deiviany Santana Santos Lima +5 more

The renin-angiotensin system (RAS) is the main endocrine and tissular component responsible for controlling cardiovascular homeostasis, which can be modulated by estrogen levels. This study investigated the effects of hormone treatments with estrogen and progestins on angiotensin-(1-7)-mediated [Ang-(1-7)] vasodilation in ovariectomized rats and the possible mechanisms involving the RAS. Female Wistar rats were divided into the following groups: sham (SHAM), ovariectomized (OVX), OVX and treated with 17β-estradiol (E2) (OE2), OVX and treated with E2 and drospirenone (OE2 + DRSP), and OVX and treated with medroxyprogesterone (MPA). Hormonal treatment was delivered via gavage for 28 days. Vascular responses to Ang-(1-7) were assessed in isolated aortic rings, and a Western blot of the thoracic aorta was used to determine the protein levels of angiotensin II (Ang II) type-1 receptor (AT1R), Ang II type-2 receptor (AT2R), Ang-(1-7) receptor (Mas), angiotensin-converting enzyme 2 (ACE2), and endothelial nitric oxide synthase (eNOS). The results showed impaired vascular reactivity caused by ovariectomy. Ang-(1-7) induced vasodilation in the OE2, OE2 + DRSP, and MPA-treated groups, while the administration of the AT2R antagonist (PD123319) or the selective Mas antagonist (A779) increased the extent of vasorelaxation induced by Ang-(1-7) in the OVX + MPA group. There were no differences in the aortic levels of AT1R or ACE2 between the groups, but the MPA group showed significantly increased levels of AT2R and eNOS. We concluded that ovariectomy induced vascular dysfunction linked to RAS regulation, and both estrogen (E2) and progestins differentially restored these parameters.