Modulation Of Renin-angiotensin-aldosterone System Research Articles

The metalloproteinase ADAM10 sheds angiotensin-converting enzyme (ACE) from the pulmonary endothelium as a soluble, functionally active convertase.

The renin-angiotensin-aldosterone system (RAAS) plays a critical role in the regulation of blood pressure and fluid balance, with angiotensin-converting enzyme (ACE) being a key transmembrane enzyme that converts angiotensin I to angiotensin II. Hence, ACE activity is an important drug target in cardiovascular pathologies such as hypertension. Our study demonstrates that human pulmonary microvascular endothelial cells (HPMECs) are an important source of proteolytically released ACE. The proteolytic release of transmembrane proteins, a process known as ectodomain shedding, is facilitated by membrane proteases called sheddases. By knockout and inhibition studies, we identified ADAM10 (A disintegrin and metalloprotease 10) as a primary sheddase responsible for ACE release in HEK293 cells. The function of ADAM10 as primary, constitutive sheddase of ACE was confirmed in HPMECs. Moreover, we demonstrated the physiological relevance of ADAM10 for ACE shedding in exvivo precision cut lung slices (PCLS) from human and mouse lungs. Notably, ADAM17 activity is not directly involved in ACE shedding but indirectly by regulating ACE mRNA and protein levels, leading to increased ADAM10-mediated ACE shedding. Importantly, soluble ACE generated by shedding is enzymatically active and can thereby participate in systemic RAAS functions. Taken together, our findings highlight the critical role of ADAM10 (directly) and ADAM17 (indirectly) in ACE shedding and RAAS modulation.

Natriuretic peptide system in hypertension: Current understandings of its regulation, targeted therapies and future challenges

The natriuretic peptide system (NPS) is the key driving force of the heart's endocrine function. Recent developments in NPS-targeted therapies have been found promising and effective against cardiovascular diseases, including hypertension. Notably, after discovering crosstalk between NPS and the renin-angiotensin-aldosterone system (RAAS), various combinations such as neprilysin/angiotensin II receptor type 1 AT1 receptor inhibitors and neprilysin/renin inhibitors have been preclinically and clinically tested against various cardiac complications. However, the therapeutic effects of such combinations on the pathophysiology of hypertension are poorly understood. Furthermore, the complicated phenomena underlying NPS regulation and function, particularly in hypertension, are still unexplored. Mounting evidence suggests that numerous regulatory mechanisms modulate the expression of NPS, which can be used as potential targets against hypertension and other cardiovascular diseases. Therefore, this review will specifically focus on epigenetic and other regulators of NPS, identifying prospective regulators that might serve as new therapeutic targets for hypertension. More importantly, it will shed light on recent developments in NPS-targeted therapies, such as M-atrial peptides, and their latest combinations with RAAS modulators, such as S086 and sacubitril-aliskiren. These insights will aid in the development of effective therapies to break the vicious cycle of high blood pressure during hypertension, ultimately addressing the expanding global heart failure pandemic.

Beauty and the beast: host microRNA-155 versus SARS-CoV-2.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection in the young and healthy usually results in an asymptomatic or mild viral syndrome, possibly through an erythropoietin (EPO)-dependent, protective evolutionary landscape. In the old and in the presence of co-morbidities, however, a potentially lethal coronavirus disease 2019 (COVID-19) cytokine storm, through unrestrained renin-angiotensin aldosterone system (RAAS) hyperactivity, has been described. Multifunctional microRNA-155 (miR-155) elevation in malaria, dengue virus (DENV), the thalassemias, and SARS-CoV-1/2, plays critical antiviral and cardiovascular roles through its targeted translational repression of over 140 genes. In the present review, we propose a plausible miR-155-dependent mechanism whereby the translational repression of AGRT1, Arginase-2 and Ets-1, reshapes RAAS towards Angiotensin II (Ang II) type 2 (AT2R)-mediated balanced, tolerable, and SARS-CoV-2-protective cardiovascular phenotypes. In addition, it enhances EPO secretion and endothelial nitric oxide synthase activation and substrate availability, and negates proinflammatory Ang II effects. Disrupted miR-155 repression of AT1R + 1166C-allele, significantly associated with adverse cardiovascular and COVID-19 outcomes, manifests its decisive role in RAAS modulation. BACH1 and SOCS1 repression creates an anti-inflammatory and cytoprotective milieu, robustly inducing antiviral interferons. MiR-155 dysregulation in the elderly, and in comorbidities, allows unimpeded RAAS hyperactivity to progress towards a particularly aggressive COVID-19 course. Elevated miR-155 in thalassemia plausibly engenders a favorable cardiovascular profile and protection against malaria, DENV, and SARS-CoV-2. MiR-155 modulating pharmaceutical approaches could offer novel therapeutic options in COVID-19.

Angiotensin II receptor blocker intake associates with reduced markers of inflammatory activation and decreased mortality in patients with cardiovascular comorbidities and COVID-19 disease.

AimsPatients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin angiotensin aldosterone system (RAAS) were suspected to influence disease severity.Methods and resultsWe analyzed 1946 consecutive patients with cardiovascular comorbidities or hypertension enrolled in one of the largest European COVID-19 registries, the Lean European Open Survey on SARS-CoV-2 (LEOSS) registry. Here, we show that angiotensin II receptor blocker intake is associated with decreased mortality in patients with COVID-19 [OR 0.75 (95% CI 0,59–0.96; p = 0.013)]. This effect was mainly driven by patients, who presented in an early phase of COVID-19 at baseline [OR 0,64 (95% CI 0,43–0,96; p = 0.029)]. Kaplan-Meier analysis revealed a significantly lower incidence of death in patients on an angiotensin receptor blocker (ARB) (n = 33/318;10,4%) compared to patients using an angiotensin-converting enzyme inhibitor (ACEi) (n = 60/348;17,2%) or patients who received neither an ACE-inhibitor nor an ARB at baseline in the uncomplicated phase (n = 90/466; 19,3%; p<0.034). Patients taking an ARB were significantly less frequently reaching the mortality predicting threshold for leukocytes (p<0.001), neutrophils (p = 0.002) and the inflammatory markers CRP (p = 0.021), procalcitonin (p = 0.001) and IL-6 (p = 0.049). ACE2 expression levels in human lung samples were not altered in patients taking RAAS modulators.ConclusionThese data suggest a beneficial effect of ARBs on disease severity in patients with cardiovascular comorbidities and COVID-19, which is linked to dampened systemic inflammatory activity.

Telmisartan ameliorates cardiac fibrosis and diastolic function in cardiorenal heart failure with preserved ejection fraction.

Chronic kidney disease (CKD) is a major contributor to the development of heart failure with preserved ejection fraction (HFpEF), whereas the underlying mechanism of cardiorenal HFpEF is still elusive. The aim of this study was to investigate the role of cardiac fibrosis in a rat model of cardiorenal HFpEF and explore whether treatment with Telmisartan, an inhibitor of renin-angiotensin-aldosterone system (RAAS), can ameliorate cardiac fibrosis and preserve diastolic function in cardiorenal HFpEF. Male rats were subjected to 5/6 subtotal nephrectomy (SNX) or sham operation (Sham), and rats were allowed four weeks to recover and form a stable condition of CKD. Telmisartan or vehicle was then administered p.o. (8 mg/kg/d) for 12 weeks. Blood pressure, brain natriuretic peptide (BNP), echocardiography, and cardiac magnetic resonance imaging were acquired to evaluate cardiac structural and functional alterations. Histopathological staining, real-time polymerase chain reaction (PCR) and western blot were performed to evaluate cardiac remodeling. SNX rats showed an HFpEF phenotype with increased BNP, decreased early to late diastolic transmitral flow velocity (E/A) ratio, increased left ventricular (LV) hypertrophy and preserved ejection fraction (EF). Pathology revealed increased cardiac fibrosis in cardiorenal HFpEF rats compared with the Sham group, while chronic treatment with Telmisartan significantly decreased cardiac fibrosis, accompanied by reduced markers of fibrosis (collagen I and collagen III) and profibrotic cytokines (α-smooth muscle actin, transforming growth factor-β1, and connective tissue growth factor). In addition, myocardial inflammation was decreased after Telmisartan treatment, which was in a linear correlation with cardiac fibrosis. Telmisartan also reversed LV hypertrophy and E/A ratio, indicating that Telmisartan can improve LV remodeling and diastolic function in cardiorenal HFpEF. In conclusion, cardiac fibrosis is central to the pathology of cardiorenal HFpEF, and RAAS modulation with Telmisartan is capable of alleviating cardiac fibrosis and preserving diastolic dysfunction in this rat model.

Vitamin D Deficiency Induces Macrophage Pro-Inflammatory Phenotype via ER Stress-Mediated Activation of Renin-Angiotensin System

Chronic inflammation and local activation of the renin-angiotensin-aldosterone system (RAAS) play a pivotal role in the pathogenesis and progression of diabetic complications. In patients with type 2 diabetes (T2DM), the prevalence of vitamin D deficiency is almost twice that of non-diabetics, and vitamin d deficiency nearly doubles the risk of developing hypertension and cardiovascular complications compared to diabetics with normal vitamin D levels. Interestingly, mice lacking the vitamin D receptor (VDR) in macrophages (KODMAC) develop renin-dependent hypertension, insulin resistance, and inflammation via up-regulation of macrophage ER stress. Macrophages also express all major components of the RAAS system. However, little is known about the regulation of macrophage-generated renin and its role in modulating the sequelae of VDR signaling in macrophage function and cytokine production. This study found that KODMAC macrophages and vitamin D-deficient macrophages have increased expression and secretion of renin, angiotensin II, ACE, and AT1 receptor and that adhesion, migration, and cytokine release were also increased. Inhibition of ER stress in KODMAC macrophages and vitamin D-deficient macrophages with 4-Phenylbutyric acid (PBA) reduced RAS gene expression and macrophage pro-inflammatory phenotype. Renin 1c gene deletion decreased macrophage adhesion, migration, and cytokine release compared to macrophages with disrupted VDR signaling. Notably, disruption of VDR signaling induced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression in macrophages, and upregulation of renin expression in response to vitamin D deficiency was blunted in PCG1α-deficient macrophages. In conclusion, our findings delineate a mechanism by which impaired VDR signaling induces ER stress to drive PGC1α-dependent expression of renin and RAAS hyperactivation, thereby altering macrophage function and cytokine production. These data implicate RAAS as an essential mediator of VDR-mediated macrophage function and support ongoing investigations of VDR and RAAS modulation as therapeutic approaches in the management of T2DM and its complications.

Hypertension and its role in COVID-19-related cerebrovascular disease

Cerebrovascular disorders such as stroke and intracerebral hemorrhage (ICH) occur in COVID-19 patients with pre-existing hypertension. Elevated blood pressure increases the risk of COVID-19-related morbidity and mortality. Although, the exact mechanisms of action are not well understood, pre-existing imbalance in the renin-angiotensin-aldosterone system (RAAS), and hypertension-induced cerebrovascular abnormalities can facilitate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infiltration into the central nervous system (CNS) leading to severe tissue damage and cerebrovascular insults. Alternatively, SARS-CoV-2 can independently affect blood flow regulation and induce cerebrovascular disease (CeVD) via binding to its receptor angiotensin converting enzyme 2 (ACE2) and modulation of RAAS. The present review systemically discusses published clinical reports and provides an overview of the potential associations between pre-existing hypertension, SARS-CoV-2 infection, and the occurrence of COVID-19-related CeVD. Early identification of high-risk patients is crucial for better point of care and prevention of COVID-19-related CeVD, morbidity and mortality.

ACE2 as a Therapeutic Target for COVID-19; its Role in Infectious Processes and Regulation by Modulators of the RAAS System.

Angiotensin converting enzyme 2 (ACE2) is the recognized host cell receptor responsible for mediating infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 bound to tissue facilitates infectivity of SARS-CoV-2; thus, one could argue that decreasing ACE2 tissue expression would be beneficial. However, ACE2 catalytic activity towards angiotensin I (Ang I) and II (Ang II) mitigates deleterious effects associated with activation of the renin-angiotensin-aldosterone system (RAAS) on several organs, including a pro-inflammatory status. At the tissue level, SARS-CoV-2 (a) binds to ACE2, leading to its internalization, and (b) favors ACE2 cleavage to form soluble ACE2: these actions result in decreased ACE2 tissue levels. Preserving tissue ACE2 activity while preventing ACE2 shredding is expected to circumvent unrestrained inflammatory response. Concerns have been raised around RAAS modulators and their effects on ACE2 expression or catalytic activity. Various cellular and animal models report conflicting results in various tissues. However, recent data from observational and meta-analysis studies in SARS-CoV-2-infected patients have concluded that RAAS modulators do not increase plasma ACE2 levels or susceptibility to infection and are not associated with more severe diseases. This review presents our current but evolving knowledge of the complex interplay between SARS-CoV-2 infection, ACE2 levels, modulators of RAAS activity and the effects of RAAS modulators on ACE2 expression.

Neurohormonal modulation as therapeutic avenue for right ventricular dysfunction in pulmonary artery hypertension: till the dawn, waiting.

Neuro-hormonal activation may lead to or be associated with pulmonary arterial hypertension (PAH) and right ventricular dysfunction. Notwithstanding whether it is the cause or the consequence of PAH-related right ventricle (RV) dysfunction neurohormonal activation contributes to significant morbidity and mortality in patients with PAH and the progression of RV dysfunction. Experimental data regarding the use of beta adrenergic blockade and renin-angiotensin aldosterone system modulation are encouraging. However, clinical studies have largely been negative or neutral; and, neuro-hormonal modulation is discouraged in patients with PAH related RV dysfunction for fear of systemic hypotension. Herein, we summarize the pathophysiological background that supports the potential role of neuro-hormonal modulation in the management of PAH related RV dysfunction; also present current clinical experience; and, discuss the need for controlled studies to move forward. Lastly, we review potential non- pharmacological modalities for neuro-hormonal modulations in PAH patients with RV dysfunction.

Pre and Post-Operative Treatments for Prevention of Atrial Fibrillation after Cardiac Surgery

Post-operative atrial fibrillation (AF) occurs in up to 40% of cardiac surgery patients and represents the most common post-operative arrhythmic complication. Post-operative AF is associated with impaired cardiac hemodynamics, increased incidence of serious complications (e.g. heart failure, stroke), prolonged hospitalization and increased healthcare costs. Therefore, treatment of post-operative AF would decrease health-care costs during hospitalization and improve the prognosis of patients following cardiovascular surgery. Current consensus guidelines recommend β-blockers, amiodarone and sotalol for post-operative AF prophylaxis. However, new pharmacological agents have been associated with a reduction in post-operative AF frequency, including inhibition of the renin angiotensin aldosterone system (RAAS) using angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), statins, antioxidant agents, magnesium supplementation and antiarrhythmic drugs. The aim of this review is to analyse and determine the efficiency of existing therapies in the reduction of post-operative AF development.

Hypertension: management perspectives

Introduction: The increasing worldwide prevalence of hypertension and the related increase in cost due to diagnosis, management and negative outcomes forces public health institutions and clinical researchers to find new strategies to improve blood pressure (BP) control. So what are the possible future perspectives for high BP management?Areas covered: Three main points are briefly discussed in this article: individualized therapy, the known genetic contribution to hypertension development and control, and the improvement of disease management, including perspectives on new antihypertensive drug development.Expert opinion: It is likely that the integration of the best available current knowledge with recent diagnostic and therapeutic achievements for the management of hypertension prevention and treatment will lead to the early detection of at-risk conditions, early diagnosis, and individualized and efficacious treatment. The most promising antihypertensive drugs currently in development are innovative renin–angiotensin–aldosterone system modulators. Further drugs have potentially interesting mechanisms of action, but renalase analogs are in the very early phases of development, and available endothelin antagonists have a poor safety profile.

Impact of angiotensin-converting enzyme-inhibitors and angiotensin receptor blockers on long-term outcome of catheter ablation for atrial fibrillation

We hypothesized that modulation of the renin-angiotensin-aldosterone system (RAAS) improves success following catheter ablation for atrial fibrillation (AF). We examined a prospective registry of consecutive patients undergoing catheter ablation of paroxysmal or persistent AF between November 2004 and December 2008. Patients were divided based on whether they were taking RAAS modulators at the time of their first procedure and examined on an intention to treat basis. There were 419 patients (222 paroxysmal and 197 persistent AF) who underwent 1.8 ± 0.9 procedures. Median follow-up from the last procedure was 1.7 (range 0.9-5.0) years. There were 142 patients on RAAS modulators; they were older, more likely to suffer from hypertension, diabetes, coronary disease, or left ventricular impairment. Overall, sinus rhythm was maintained in 73.2% of those taking RAAS modulators vs. 77.6% of those taking none (P = 0.304). Multivariate analysis showed no impact of RAAS modulators [hazard ratios (HR): 1.97, CI: 0.56-6.89, P = 0.290] but also no effect of hypertension, ischaemic heart disease, left ventricular impairment, or diabetes that should have confounded results (persistent AF was found to predict failure; HR: 0.34, CI: 0.14-0.84, P = 0.020). Subgroup analysis of patients with risk factors for developing AF (hypertension, coronary artery disease, left ventricular impairment, or diabetes) found no benefit in this context, with sinus rhythm maintained in 73.2% of those taking RAAS modulators compared with 69.9% of those taking none (P = 0.574). Modulation of the RAAS does not appear to affect maintenance of sinus rhythm following catheter ablation of AF.

Glycosaminoglycans: use in treatment of diabetic nephropathy.

Glycosaminoglycans: use in treatment of diabetic nephropathy.