scholarly journals Valsartan and Sacubitril Combination Treatment Enhances Collagen Production in Older Adult Human Skin Cells

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 688-689
Author(s):  
Sela Marin ◽  
Lolita S Nidadavolu ◽  
Jeremy D Walston ◽  
Daniele Gilkes ◽  
Peter M Abadir ◽  
...  
Keyword(s):  
Human Skin ◽  
Older Adult ◽  
Renin Angiotensin System ◽  
Young Individual ◽  
Concomitant Treatment ◽  
Angiotensin System ◽  
Collagen Production ◽  
Renin Angiotensin ◽  
Skin Collagen ◽  
The Impact

Abstract Collagen is a major component of the skin’s support system, allowing for firmness, elasticity, and mechanical strength. In older adults, skin collagen production decreases significantly, and is associated with increased sagging, wrinkling, and thinning. The Renin Angiotensin System (RAS) is a key hormonal system that changes with age and affects multiple organ systems. While primary health benefits of Angiotensin (Ang) receptor type1 (AT1 R) blockers (ARBs) are believed to arise from systemic effects on blood pressure. There exists a skin-specific Renin Angiotensin System (RAS), but the impact of ARBs on older skin is unknown. Human skin fibroblasts from individuals aged 2 (young individual) and 57 (older individual) were treated with drugs that alter RAS: Valsartan (an ARB) and neprilysin inhibitor Sacubitril. Fibroblast proliferation and collagen production was quantified in response to the drug treatment using fluorescence microscopy. Fibroblasts from 57-year-old individuals were slower to proliferate and had less collagen content as compared to fibroblasts from young individual. Valsartan alone treatment had no effect on collagen production from young or old fibroblasts. In contrast, Sacubitril treatment increased collagen production by approximately three-fold in young (2.87 ± 0.27 RFU, P<.0001), and older (2.93 ± 0.53 RFU, P<.0001) fibroblasts. Concomitant treatment with Valsartan and Sacubitril increased collagen production by five-fold increase (5.36 ± 1.08 RFU, P<.0001) in young fibroblasts, and four-fold (4.18 ± 0.96 RFU, P=.003) in older cells. This study demonstrates a novel use for the widely prescribed drug combination, Sacubitril and Valsartan, which significantly improves collagen production in older adult fibroblasts.

scholarly journals Outcomes of COVID-19 Hospitalized Patients Previously Treated with Renin-Angiotensin System Inhibitors

2020 ◽  
Vol 9 (11) ◽  
pp. 3472 ◽  
Author(s):  
Elena-Mihaela Cordeanu ◽  
Lucas Jambert ◽  
Francois Severac ◽  
Hélène Lambach ◽  
Jonathan Tousch ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Severe Pneumonia ◽  
University Hospital ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Previously Treated ◽  
The Impact ◽  
Harmful Effects ◽  
Observation Period

(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates respiratory epithelium through angiotensin-converting enzyme-2 binding, raising concerns about the potentially harmful effects of renin–angiotensin system inhibitors (RASi) on Human Coronavirus Disease 2019 (COVID-19) evolution. This study aimed to provide insight into the impact of RASi on SARS-CoV-2 outcomes in patients hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult patients with SARS-CoV-2 infection admitted to a university hospital in France. The observation period ended at hospital discharge. (3) Results: During the study period, 943 COVID-19 patients were admitted to our institution, of whom 772 were included in this analysis. Among them, 431 (55.8%) had previously known hypertension. The median age was 68 (56–79) years. Overall, 220 (28.5%) patients were placed under mechanical ventilation and 173 (22.4%) died. According to previous exposure to RASi, we defined two groups, namely, “RASi” (n = 282) and “RASi-free” (n = 490). Severe pneumonia (defined as leading to death and/or requiring intubation, high-flow nasal oxygen, noninvasive ventilation, and/or oxygen flow at a rate of ≥5 L/min) and death occurred more frequently in RASi-treated patients (64% versus 53% and 29% versus 19%, respectively). However, in a propensity score-matched cohort derived from the overall population, neither death (hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.57–1.50), p = 0.76) nor severe pneumonia (HR 1.03 (95%CI 0.73–1.44), p = 0.85) were associated with RASi therapy. (4) Conclusion: Our study showed no correlation between previous RASi treatment and death or severe COVID-19 pneumonia after adjustment for confounders.

Effects of Tokishakuyakusan, Keishibukuryogan, Shakuyakukanzoto and Unkeito on Ovarian Endothelin, Renin and Angiotensin II in Pregnant Mare's Serum Gonadotropin-treated Immature Rats

1992 ◽  
Vol 20 (02) ◽  
pp. 175-179 ◽  
Author(s):  
Satoshi Usuki ◽  
Yoshie Usuki ◽  
Junko Tanaka ◽  
Yuko Kawakura
Keyword(s):  
Angiotensin Ii ◽  
Herbal Medicines ◽  
Renin Angiotensin System ◽  
Concomitant Treatment ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Immature Rats ◽  
Serum Gonadotropin ◽  
Peptide System

We have previously proposed the ovarian ERAANPS (endothelin-renin-angiotensin-atrial natriuretic peptide system). The present study was undertaken to examine in vivo the effects of herbal medicines [Tokishakuyakusan (TS), Keishibukuryogan (KB), Shakuyakukanzoto (SK) and Unkeito (UT)] on endothelin-l (ET), renin and angiotensin II (A II) in the ovaries, of immature rats treated with 10 IU PMS for 48 h. ET and all components of renin-angiotensin system (RAS) were found at high levels in the ovary. Concomitant treatment with PMS plus TS, KB, SK or UT, especially TS and UT, tended to decrease the ET levels in ovary, while components of RAS tended to increase. However, ET, renin and A II levels in plasma were not at all affected after treatment with TS, KB, SK or UT. These results suggest that TS, KB, SK or UT may regulate the ovarian ERAANPS.

Gene variants of the renin–angiotensin system and hypertension: from a trough of disillusionment to a welcome phase of enlightenment?

2010 ◽  
Vol 118 (8) ◽  
pp. 487-506 ◽  
Author(s):  
Gavin R. Norton ◽  
Richard Brooksbank ◽  
Angela J. Woodiwiss
Keyword(s):  
Association Studies ◽  
Large Population ◽  
Renin Angiotensin System ◽  
Human Populations ◽  
Incomplete Penetrance ◽  
Gene Variants ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Ras Genes ◽  
The Impact

There is substantial evidence to suggest that BP (blood pressure) is an inherited trait. The introduction of gene technologies in the late 1980s generated a sharp phase of over-inflated prospects for polygenic traits such as hypertension. Not unexpectedly, the identification of the responsible loci in human populations has nevertheless proved to be a considerable challenge. Common variants of the RAS (renin–angiotensin system) genes, including of ACE (angiotensin-converting enzyme) and AGT (angiotensinogen) were some of the first shown to be associated with BP. Presently, ACE and AGT are the only gene variants with functional relevance, where linkage studies showing relationships with hypertension have been reproduced in some studies and where large population-based and prospective studies have demonstrated these genes to be predictors of hypertension or BP. Nevertheless, a lack of reproducibility in other linkage and association studies has generated scepticism that only a concerted effort to attempt to explain will rectify. Without these explanations, it is unlikely that this knowledge will translate into the clinical arena. In the present review, we show that many of the previous concerns in the field have been addressed, but we also argue that a considerable amount of careful thought is still required to achieve enlightenment with respect to the role of RAS genes in hypertension. We discuss whether the previously identified problems of poor study design have been completely addressed with regards to the impact of ACE and AGT genes on BP. In the context of RAS genes, we also question whether the significance of ‘incomplete penetrance’ through associated environmental, phenotypic or physiological effects has been duly accounted for; whether appropriate consideration has been given to epistatic interactions between genes; and whether future RAS gene studies should consider variation across the gene by evaluating ‘haplotypes’.

P1661The myocardial tissue Renin-Angiotensin-System (RAS) of the failing heart

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
N Pavo ◽  
H Arfsten ◽  
R Wurm ◽  
S Prausmueller ◽  
G Spinka ◽  
...  
Keyword(s):  
Disease Progression ◽  
Renin Angiotensin System ◽  
Inhibitor Therapy ◽  
Myocardial Tissue ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Failing Heart ◽  
End Stage ◽  
The Impact ◽  
Nep Inhibition

Abstract Background Prognosis of patients with HFrEF remains poor despite recent advances in pharmacologic therapy as the introduction of the angiotensin-receptor neprilysin-inhibitor (ARNI). The Renin-Angiotensin-System (RAS) is dysregulated in HF with elevated AngII levels as a central driver of disease progression. The myocardium is capable of synthesizing all RAS components resulting in tissue specific angiotensin levels. Neprilysin (NEP) catalyzes the generation of Ang1–7 which counteracts the deleterious effects of AngII. Myocardial tissue angiotensins of the failing heart and the role of long-lasting RAS-inhibitor therapy and particularly NEP inhibition on tissue RAS have not been investigated yet. Methods Concentrations of AngI, AngII, Ang1–7, AngIII, Ang1–5 and AngIV (RAS-fingerprints) were investigated in myocardial samples of end-stage HFrEF patients undergoing heart transplantation with a mass-spectrometry based method. Patients were stratified according to background therapy with RAS-inhibitors and variables were compared by a non-parametrical test. Results A total of 30 patients were included (n=6 without RAS-blockade, n=16 with ACE-I, n=6 with ARB and n=2 with ARNI). Median age was 55 (IQR 45–63) years and 87% of patients were male. 40% of patients had an ischemic etiology of HF, median NT-proBNP levels were 3498pg/ml (IQR 1761–8400). Tissue RAS patterns were visually similar between all groups (Figure 1). Myocardial AngI, Ang1–7, Ang1–5 and AngIV levels were below the detection limit for all samples. Median tissue AngII and AngIII concentrations across all samples were 83.1pg/ml (IQR 29.3–196.6) and 26.4pg/ml (IQR 5.0–64.5). Despite different background RAS-inhibitor therapy, AngII and AngIII levels were comparable between all groups [median (IQR) in pg/ml – AngII: 51.5 (41.5–123.8) vs. 72.4 (28.5–177.6) vs. 176.1 (22.4–286.8) vs. 266.0 (108.2–423.8); p=ns and 26.4 (5.0–89.2) vs. 23.2 (5.0–59.3) vs. 39.4 (5.0–94.3) vs. 105.9 (46.5–165.3); p=ns for no therapy, ACE-I, ARB and ARNI respectively]. Figure 1. RAS-fingerprints of the failing heart according to RAS-inhibiton. Numbers in brackets indicate the specific angiotensin peptides. Side of spheres and numbers beside represent absolute concentrations of angiotensins (pg/ml, median value). Conclusions Although in the plasma of HFrEF patients only AngI and AngII are detectable at substantial concentrations, the predominant angiotensins of the failing heart are AngII and AngIII. AngII levels are high in the failing heart supporting the hypothesis that excess AngII is involved in disease progression. AngIII similarly increases cardiac sympathetic activity assumedly potentiating further deteoriation. The modality of long established RAS-inhibitor therapy in end-stage HF, particularly the inhibition of NEP, seems to have no (more) influence on myocardial tissue RAS regulation. The impact of NEP inhibition by ARNI on tissue RAS enzymes and mechanism of action need to be further investigated.

scholarly journals Modeling the Molecular Impact of SARS-CoV-2 Infection on the Renin-Angiotensin System

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1367
Author(s):  
Fabrizio Pucci ◽  
Philippe Bogaerts ◽  
Marianne Rooman
Keyword(s):  
Renin Angiotensin System ◽  
Therapeutic Strategies ◽  
Spike Protein ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Pathogenic Mechanisms ◽  
Renin Angiotensin ◽  
Factors Associated ◽  
Ras Blockers ◽  
The Impact

SARS-CoV-2 infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We used our model to analyze the impact of SARS-CoV-2 infection on RAS, which we modeled through a downregulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2, and angiotensin 1–7 peptide, on COVID-19 patients; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others. Our model and its predictions constitute a valuable framework for in silico testing of hypotheses about the COVID-19 pathogenic mechanisms and the effect of drugs aiming to restore RAS functionality.

scholarly journals Kallikrein–kinin system as the dominant mechanism to counteract hyperactive renin–angiotensin system

2017 ◽  
Vol 95 (10) ◽  
pp. 1117-1124 ◽  
Author(s):  
Domenico Regoli ◽  
Fernand Gobeil
Keyword(s):  
Renin Angiotensin System ◽  
Biologically Active ◽  
Ang Ii ◽  
Kinin System ◽  
Angiotensin System ◽  
Dominant Mechanism ◽  
Renin Angiotensin ◽  
First Choice ◽  
Kallikrein Kinin System ◽  
The Impact

The renin–angiotensin system (RAS) generates, maintains, and makes worse hypertension and cardiovascular diseases (CVDs) through its biologically active component angiotensin II (Ang II), that causes vasoconstriction, sodium retention, and structural alterations of the heart and the arteries. A few endogenous vasodilators, kinins, natriuretic peptides, and possibly angiotensin (1-7), exert opposite actions and may provide useful therapeutic agents. As endothelial autacoids, the kinins are potent vasodilators, active natriuretics, and protectors of the endothelium. Indeed, the kallikrein–kinin system (KKS) is considered the dominant mechanism for counteracting the detrimental effects of the hyperactive RAS. The 2 systems, RAS and KKS, are controlled by the angiotensin-converting enzyme (ACE) that generates Ang II and inactivates the kinins. Inhibitors of ACE can reduce the impact of Ang II and potentiate the kinins, thus contributing to restore the cardiovascular homeostasis. In the last 20 years, ACE-inhibitors (ACE-Is) have become the drugs of first choice for the treatments of the major CVDs. ACE-Is not only reduce blood pressure, as sartans also do, but by protecting and potentiating the kinins, they can reduce morbidity and mortality and improve the quality of life for patients with CVDs. This paper provides a brief review of the literature on this topic.

scholarly journals The brain renin-angiotensin system and cardiovascular responses to stress: insights from transgenic rats with low brain angiotensinogen

2012 ◽  
Vol 113 (12) ◽  
pp. 1929-1936 ◽  
Author(s):  
Amy C. Arnold ◽  
Atsushi Sakima ◽  
Sherry O. Kasper ◽  
Sherry Vinsant ◽  
Maria Antonia Garcia-Espinosa ◽  
...  
Keyword(s):  
Stress Responses ◽  
Renin Angiotensin System ◽  
Cardiovascular Responses ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Brain Peptides ◽  
The Impact ◽  
The Brain

The renin-angiotensin system (RAS) has been identified as an attractive target for the treatment of stress-induced cardiovascular disorders. The effects of angiotensin (ANG) peptides during stress responses likely result from an integration of actions by circulating peptides and brain peptides derived from neuronal and glial sources. The present review focuses on the contribution of endogenous brain ANG peptides to pathways involved in cardiovascular responses to stressors. During a variety of forms of stress, neuronal pathways in forebrain areas containing ANG II or ANG-(1–7) are activated to stimulate descending angiotensinergic pathways that increase sympathetic outflow to increase blood pressure. We provide evidence that glia-derived ANG peptides influence brain AT1 receptors. This appears to result in modulation of the responsiveness of the neuronal pathways activated during stressors that elevate circulating ANG peptides to activate brain pathways involving descending hypothalamic projections. It is well established that increased cardiovascular reactivity to stress is a significant predictor of hypertension and other cardiovascular diseases. This review highlights the importance of understanding the impact of RAS components from the circulation, neurons, and glia on the integration of cardiovascular responses to stressors.

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