Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling

Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1–7-dependent manner. Whether apelin antagonizes the over-activation of the renin–angiotensin system in the heart remains elusive. In this study we show that the detrimental effects of angiotensin II (Ang II) were exacerbated in the hearts of aged apelin-gene-deficient mice. Ang II-mediated cardiac dysfunction and hypertrophy were augmented in apelin knockout mice. The loss of apelin increased the ratio of angiotensin-converting enzyme (ACE) to ACE2 expression in the Ang II-stressed hearts, and Ang II-induced cardiac fibrosis was markedly enhanced in apelin knockout mice. mRNA expression of pro-fibrotic genes, such as transforming growth-factor beta (TGF-β) signaling, were significantly upregulated in apelin knockout hearts. Consistently, treatment with the ACE-inhibitor Captopril decreased cardiac contractility in apelin knockout mice. In vitro, apelin ameliorated Ang II-induced TGF-β expression in primary cardiomyocytes, accompanied with reduced hypertrophy. These results provide direct evidence that endogenous apelin plays a crucial role in suppressing Ang II-induced cardiac dysfunction and pathological remodeling.

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Angiotensin II induces apoptosis in human and rat alveolar epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.276.5.l885 ◽

1999 ◽

Vol 276 (5) ◽

pp. L885-L889 ◽

Cited By ~ 43

Author(s):

Rongqi Wang ◽

Alex Zagariya ◽

Olivia Ibarra-Sunga ◽

Claudia Gidea ◽

Edmund Ang ◽

...

Keyword(s):

Angiotensin Ii ◽

Epithelial Cells ◽

Angiotensin Converting Enzyme ◽

Enzyme Inhibitor ◽

Alveolar Epithelial Cells ◽

Receptor Subtypes ◽

Ang Ii ◽

Converting Enzyme ◽

Alveolar Epithelial

Recent work from this laboratory demonstrated potent inhibition of apoptosis in human alveolar epithelial cells (AECs) by the angiotensin-converting enzyme inhibitor captopril [B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O. Ibarra-Sunga, M. Papp, K. Flynn, and G. Filippatos. Am. J. Physiol. 275 ( Lung Cell. Mol. Physiol. 19): L1013–L1017, 1998]. On this basis, we hypothesized that apoptosis in this cell type might be induced by angiotensin II (ANG II) through its interaction with the ANG II receptor. Purified ANG II induced dose-dependent apoptosis in both the human AEC-derived A549 cell line and in primary type II pneumocytes isolated from adult Wistar rats as detected by nuclear and chromatin morphology, caspase-3 activity, and increased binding of annexin V. Apoptosis also was induced in primary rat AECs by purified angiotensinogen. The nonselective ANG II-receptor antagonist saralasin completely abrogated both ANG II- and angiotensinogen-induced apoptosis at a concentration of 50 μg/ml. With RT-PCR, both cell types expressed the ANG II-receptor subtypes 1 and 2 and angiotensin-converting enzyme (ACE). The nonthiol ACE inhibitor lisinopril blocked apoptosis induced by angiotensinogen, but not apoptosis induced by purified ANG II. These data demonstrate the presence of a functional ANG II-dependent pathway for apoptosis in human and rat AECs and suggest a role for the ANG II receptor and ACE in the induction of AEC apoptosis in vivo.

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Enalapril decreases angiotensin II receptors in subfornical organ of SHR

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.256.6.h1609 ◽

1989 ◽

Vol 256 (6) ◽

pp. H1609-H1614 ◽

Cited By ~ 3

Author(s):

A. J. Nazarali ◽

J. S. Gutkind ◽

F. M. Correa ◽

J. M. Saavedra

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Enzyme Inhibitor ◽

Area Postrema ◽

Subfornical Organ ◽

Ang Ii ◽

Converting Enzyme ◽

Converting Enzyme Inhibitors ◽

Wky Rats ◽

Enalapril Treatment

We studied brain angiotensin II (ANG II) receptors by quantitative autoradiography in adult normotensive Wistar-Kyoto (WKY) rats and in spontaneously hypertensive rats (SHR) after treating the rats with the converting-enzyme inhibitor enalapril, 25 mg/kg, po daily for 14 days. Enalapril treatment decreased blood pressure in only SHR, inhibited plasma angiotensin-converting enzyme activity by 85%, and increased plasma ANG I concentration and renin activity in both WKY and SHR. In the untreated SHR animals, ANG II receptor concentrations were higher in the subfornical organ, the area postrema, the nucleus of the solitary tract, and the inferior olive when compared with the untreated WKY rats. Enalapril treatment produced a large decrease in only subfornical organ ANG II receptors of SHR. The selective reversal of the alteration in subfornical organ ANG II receptors in SHR may indicate a decreased central response to ANG II and may be related to the mode of action of angiotensin-converting enzyme inhibitors in this model.

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Angiotensin-Converting Enzyme 2 as a Possible Correlation between COVID-19 and Periodontal Disease

Applied Sciences ◽

10.3390/app10186224 ◽

2020 ◽

Vol 10 (18) ◽

pp. 6224 ◽

Cited By ~ 1

Author(s):

Leonardo Mancini ◽

Vincenzo Quinzi ◽

Stefano Mummolo ◽

Giuseppe Marzo ◽

Enrico Marchetti

Keyword(s):

Angiotensin Ii ◽

Inflammatory Response ◽

Angiotensin Converting Enzyme ◽

Transforming Growth Factor ◽

Tissue Injury ◽

Interleukin 2 ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Cell Functions

SARS-CoV-2 propagation in the world has led to rapid growth and an acceleration in the discoveries and publications of various interests. The main focus of a consistent number of studies has been the role of angiotensin-converting enzyme 2 (ACE2) in binding the virus and its role in expression of the inflammatory response after transmission. ACE2 is an enzyme involved in the renin–angiotensin system (RAS), whose key role is to regulate and counter angiotensin-converting enzyme (ACE), reducing the amount of angiotensin II and increasing angiotensin 1–7 (Ang1–7), making it a promising drug target for treating cardiovascular diseases. The classical RAS axis, formed by ACE, angiotensin II (Ang II), and angiotensin receptor type 1 (AT1), activates several cell functions and molecular signalling pathways related to tissue injury and inflammation. In contrast, the RAS axis composed of ACE2, Ang1–7, and Mas receptor (MasR) exerts the opposite effect concerning the inflammatory response and tissue fibrosis. Recent studies have shown the presence of the RAS system in periodontal sites where osteoblasts, fibroblasts, and osteoclasts are involved in bone remodelling, suggesting that the role of ACE2 might have a fundamental function in the under- or overexpression of cytokines such as interleukin-6 (IL-6), interleukin-7 (IL-7), tumour necrosis factor alpha (TNF-α), interleukin-2 (IL-2), interleukin-1 beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta (TGF-β), associated with a periodontal disorder, mainly during coinfection with SARS-CoV-2, where ACE2 is underexpressed and cannot form the ACE2–Ang1–7–MasR axis. This renders the patient unresponsive to an inflammatory process, facilitating periodontal loss.

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Chymase-dependent production of angiotensin II: an old enzyme in old hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00534.2016 ◽

2017 ◽

Vol 312 (2) ◽

pp. H223-H231 ◽

Cited By ~ 17

Author(s):

Ghezal Froogh ◽

John T. Pinto ◽

Yicong Le ◽

Sharath Kandhi ◽

Yeabsra Aleligne ◽

...

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Renin Angiotensin System ◽

Ang Ii ◽

Aged Rats ◽

Converting Enzyme ◽

Local Formation ◽

Angiotensin System ◽

Renin Angiotensin ◽

Age Dependent

Age-dependent alteration of the renin-angiotensin system (RAS) and generation of angiotensin II (Ang II) are well documented. By contrast, RAS-independent generation of Ang II in aging and its responses to exercise have not been explored. To this end, we examined the effects of chymase, a secretory serine protease, on the angiotensin-converting enzyme (ACE)-independent conversion of Ang I to Ang II. We hypothesized that age-dependent alteration of cardiac Ang II formation is chymase dependent in nature and is prevented by exercise training. Experiments were conducted on hearts isolated from young (3 mo), aged sedentary (24 mo), and aged rats chronically exercised on a treadmill. In the presence of low Ang I levels and downregulation of ACE expression/activity, cardiac Ang II levels were significantly higher in aged than young rats, suggesting an ACE-independent response. Aged hearts also displayed significantly increased chymase expression and activity, as well as upregulation of tryptase, a biological marker of mast cells, confirming a mast cell-sourced increase in chymase. Coincidently, cardiac superoxide produced from NADPH oxidase (Nox) was significantly enhanced in aged rats and was normalized by exercise. Conversely, a significant reduction in cardiac expression of ACE2 followed by lower Ang 1-7 levels and downregulation of the Mas receptor (binding protein of Ang 1-7) in aged rats were completely reversed by exercise. In conclusion, local formation of Ang II is increased in aged hearts, and chymase is primarily responsible for this increase. Chronic exercise is able to normalize the age-dependent alterations via compromising chymase/Ang II/angiotensin type 1 receptor/Nox actions while promoting ACE2/Ang 1-7/MasR signaling. NEW & NOTEWORTHY Aging increases angiotensin-converting enzyme (ACE)-independent production of cardiac angiotensin II (Ang II), a response that is driven by chymase in an exercise-reversible manner. These findings highlight chymase, in addition to ACE, as an important therapeutic target in the treatment and prevention of Ang II-induced deterioration of cardiac function in the elderly. Listen to this article's corresponding podcast @ http://ajpheart.podbean.com/e/renin-angiotensin-system-signaling-in-aged-and-age-exercised-rats/ .

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A REVIEW ON COMPARATIVE STUDY ON THE SAFETY AND EFFECTIVENESS OF SACUBITRIL-VALSARTAN COMBINATION WITH ACE/ARB THERAPY IN CARDIAC PATIENTS

International Journal of Pharmaceutical and Biological Science Archive ◽

10.32553/ijpba.v7i2.120 ◽

2019 ◽

Vol 7 (2) ◽

Author(s):

Bhagya Suresh ◽

Mathew George ◽

Lincy Joseph

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Left Ventricular ◽

At1 Receptor ◽

Receptor Blocker ◽

Left Ventricular Ejection ◽

Ang Ii ◽

Converting Enzyme ◽

Cv Disease

Cardiovascular (CV) disease is a major cause of morbidity and mortality in the developing and the developed world, and represents a major barrier to sustainable human development. Ischemic heart disease, cerebrovascular disease, cardiomyopathy and heart failure (HF), and hypertension among others represent major forms of CV disease. Heart failure (HF) is among the key contributors to the CV-related health care burden, a uninterrupted concern despite the utilization of clinically tried guideline-directed therapies. The most common cause for HF is reduced left cavum heart muscle perform. ARBs produce equivalent mortality benefits with fewer adverse effects than ACE inhibitors. Angiotensin converting enzyme (ACEI) reduces the combined risk of death or hospitalization, slow progression of HF, and reduced rate of reinfarction. Sacubitril/valsartan could be a first-in-class twin action molecule of the neprilysin (NEP) substance sacubitril (AHU-377) and therefore the angiotensin II (Ang II) sort one (AT1) receptor blocker (ARB) valsartan. The beneficial antihypertensive and HF effects of sacubitril/valsartan are mediated through the inhibition of NEP in catabolizing the natriuretic peptides (NPs) and the blockade of Ang II, AT1 receptor with valsartan. These actions of sacubitril/ valsartan end in general dilation and inflated symptoms and symptoms, resulting in decrease in peripheral tube resistance and plasma volume contraction, all necessary actions for the lowering of BP and improving HF symptoms. Keywords: cardiovascular disease, left ventricular ejection fraction, angiotensin II receptor blocker, angiotensin converting enzyme, sacubitril/valsartan.

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Electroacupuncture Improved Chronic Cerebral Hypoperfusion-Induced Anxiety-Like Behavior and Memory Impairments in Spontaneously Hypertensive Rats by Downregulating the ACE/Ang II/AT1R Axis and Upregulating the ACE2/Ang-(1-7)/MasR Axis

Neural Plasticity ◽

10.1155/2020/9076042 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Peipei Feng ◽

Zemin Wu ◽

Hao Liu ◽

Yafang Shen ◽

Xu Yao ◽

...

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Spontaneously Hypertensive Rats ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Ang Ii ◽

Converting Enzyme ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Memory Impairments

Electroacupuncture (EA) can effectively alleviate anxiety disorders and memory impairments caused by various neurodegenerative diseases; however, the molecular mechanisms underlying its neuroprotective effects are unclear. Previous studies have shown that the renin-angiotensin system (RAS) comprises of two axes with mutual antagonism: the classical angiotensin converting enzyme/angiotensin II/angiotensin II type 1 receptor (ACE/Ang II/AT1R) axis and the protective angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor (ACE2/Ang-(1-7)/MasR) axis. In this study, we observed that chronic cerebral hypoperfusion (CCH) mediated anxiety-like behavior and memory impairments in spontaneously hypertensive rats (SHR) via upregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and the partial hippocampal protective axis (ACE2/Ang-(1-7)). However, Ang II levels were much higher than those of Ang-(1–7), indicating that the ACE/Ang II/AT1R axis plays a dominant role in the comorbidity of CCH and hypertension. Moreover, candesartan cilexetil (Canc) and perindopril (Peril) were used as positive control drugs. We found that EA, Canc, and Peril attenuated CCH-induced anxiety-like behavior and memory impairments in SHR, potentially via downregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and upregulation of the whole hippocampal protective axis (ACE2/Ang-(1-7)/MasR). These results suggest that EA therapy for CCH with hypertension may be mediated by two hippocampal RAS axes.

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Functional role of local angiotensin-converting enzyme (ACE) in adrenal catecholamine secretion in vivo

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y99-094 ◽

1999 ◽

Vol 77 (11) ◽

pp. 878-885 ◽

Cited By ~ 2

Author(s):

Nobuharu Yamaguchi ◽

Daniel Martineau ◽

Stéphane Lamouche ◽

Richard Briand

Keyword(s):

Angiotensin Ii ◽

Adrenal Gland ◽

Angiotensin Converting Enzyme ◽

Venous Blood Flow ◽

Dependent Manner ◽

Converting Enzyme ◽

Left Adrenal Gland ◽

Angiotensin I ◽

Aortic Blood

The aim of the present study was to investigate whether exogenous angiotensin I (AngI) is locally converted to angiotensin II (AngII), which in turn results in an increase in the adrenal catecholamine (CA) secretion in the adrenal gland in anesthetized dogs. Plasma CA concentrations in adrenal venous and aortic blood were determined by an HPLC-electrochemical method. Adrenal venous blood flow was measured by gravimetry. Local administration of AngI (0.0062 to 6.2 µg, 0.0096 to 9.6 µM) to the left adrenal gland resulted in significant increases in CA output in a dose-dependent manner. Following administration of 0.62 µg (0.96 µM) of AngI, adrenal epinephrine and norepinephrine outputs increased from 20.8 ± 13.6 to 250.9 ± 96.4 ng·min-1·g-1 (p < 0.05, n = 5) and from 2.8 ± 1.7 to 29.6 ± 11.1 ng·min-1·g-1 (p < 0.05, n = 5), respectively. From the same left adrenal gland, the output of AngII increased from -0.02 ± 0.04 to 26.39 ± 11.38 ng·min-1·g-1 (p < 0.05, n = 5), while plasma concentrations of AngII in aortic blood remained unchanged. In dogs receiving captopril (12.5 µg, 0.5 mM) 10 min prior to AngI, the net amounts of CA and AngII secreted during the first 3 min after AngI were diminished by about 80% (p < 0.05, n = 5) compared with those obtained from the control group. There was a close correlation (r2 = 0.91, n = 6) between the net increases in AngII and CA outputs induced by AngI. The results indicate that the local angiotensin converting enzyme is functionally involved in regional AngII formation in the canine adrenal gland in vivo. The study suggests that AngII thus generated may play a role in the local regulation of adrenal CA secretion.Key words: angiotensin I, angiotensin II, captopril, adrenal gland, anesthetized dog.

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Acute effects of angiotensin-converting enzyme inhibition versus angiotensin II receptor blockade on cardiac sympathetic activity in patients with heart failure

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00095.2017 ◽

2017 ◽

Vol 313 (4) ◽

pp. R410-R417 ◽

Cited By ~ 3

Author(s):

Eduardo R. Azevedo ◽

Susanna Mak ◽

John S. Floras ◽

John D. Parker

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Sympathetic Activity ◽

Ang Ii ◽

Converting Enzyme ◽

Acute Effects ◽

Beneficial Effects ◽

Patients With Heart Failure ◽

Total Body

The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ANG II) receptor antagonists in patients with heart failure secondary to reduced ejection fraction (HFrEF) are felt to result from prevention of the adverse effects of ANG II on systemic afterload and renal homeostasis. However, ANG II can activate the sympathetic nervous system, and part of the beneficial effects of ACE inhibitors and ANG II antagonists may result from their ability to inhibit such activation. We examined the acute effects of the ACE inhibitor captopril (25 mg, n = 9) and the ANG II receptor antagonist losartan (50 mg, n = 10) on hemodynamics as well as total body and cardiac norepinephrine spillover in patients with chronic HFrEF. Hemodynamic and neurochemical measurements were made at baseline and at 1, 2, and 4 h after oral dosing. Administration of both drugs caused significant reductions in systemic arterial, cardiac filling, and pulmonary artery pressures ( P < 0.05 vs. baseline). There was no significant difference in the magnitude of those hemodynamic effects. Plasma concentrations of ANG II were significantly decreased by captopril and increased by losartan ( P < 0.05 vs. baseline for both). Total body sympathetic activity increased in response to both captopril and losartan ( P < 0.05 vs. baseline for both); however, there was no change in cardiac sympathetic activity in response to either drug. The results of the present study do not support the hypothesis that the acute inhibition of the renin-angiotensin system has sympathoinhibitory effects in patients with chronic HFrEF.

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