Alamandine Protects the Heart Against Reperfusion Injury via the MrgD Receptor

Park, Byung Mun; Phuong, Hoang Thi Ai; Yu, Longquan; Kim, Suhn Hee

doi:10.1253/circj.cj-17-1381

Cited by 22 publications

(17 citation statements)

References 35 publications

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“…These results indicated that alamandine improved LPS-induced cardiac dysfunction and increased cardiac contractility. 23) Additionally, alamandine has cardioprotective effects on ischemia-reperfusion Injury by activating the antioxidant and antiapoptotic enzymes via the MrgD receptor. Alamandine improved reperfusion-induced changes in LVEDP, LVDP, ±dP/dt, and coronary blood flow.…”

Section: Discussionmentioning

confidence: 99%

Effect of Prolonged Infusion of Alamandine on Cardiovascular Parameters and Cardiac ACE2 Expression in a Rat Model of Renovascular Hypertension

Hekmat

Zare

Moravej

et al. 2019

Biological & Pharmaceutical Bulletin

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Alamandine is a new member of the angiotensin family. Here, we studied the mRNA and protein expression of cardiac angiotensin-converting enzyme 2 (ACE2) in the chronic phase of a rat model of 2-kidney, 1-clip hypertension (2K1C), and the effects of 2-week alamandine infusion on blood pressure, cardiac indices, and ACE2 mRNA and protein expression in the hearts. The rats were subjected to to sham-operation or placement of plexiglass clips around the left renal artery. Alamandine, at a dose of 600 µg/kg/d, was administered for 2 weeks via an osmotic mini-pump. At 18 weeks, after induction of hypertension, blood pressure and cardiac indices of contractility were measured using a Powerlab Physiograph system. The ACE2 mRNA and protein levels were determined using real time-PCR and Western blotting, respectively. In the hypertensive rats, alamandine caused a significant decrease in systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.001), left ventricular end-diastolic pressure (p < 0.001) and, left ventricular systolic pressure (p < 0.001) and increase in the maximum rate of pressure change in the left ventricle (dP/dt(max)) (p < 0.05). Also, the ACE2 mRNA expression in the heart increased in the hypertensive rats compared to the normotensive rats (p < 0.05), and alamandine restored this to normal values, although these changes were only seen at the mRNA and not the protein level. Histological analysis of cardiac tissue confirmed that alamandine decreased cardiac fibrosis and hypertrophy in 2K1C hypertensive rats. Our results indicate that alamandine, which acts as a depressor arm of the renin-angiotensin system, could be developed for treating hypertension.

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Section: Discussionmentioning

confidence: 99%

Effect of Prolonged Infusion of Alamandine on Cardiovascular Parameters and Cardiac ACE2 Expression in a Rat Model of Renovascular Hypertension

Hekmat

Zare

Moravej

et al. 2019

Biological & Pharmaceutical Bulletin

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“…We observed that MrgD KO mice presented a reduction in atrial natriuretic peptide mRNA with no changes in brain natriuretic peptide mRNA. Accordingly, Park et al (23) have recently shown that alamandine can stimulate atrial natriuretic peptide secretion in isolated atria, and this effect was completely blocked by a MrgD receptor antagonist. The reduction of atrial natriuretic peptide expression in MrgD KO mice could be implicated in the pathogenesis of DCM observed in these animals.…”

Section: H129mentioning

confidence: 99%

Genetic deletion of the alamandine receptor MRGD leads to dilated cardiomyopathy in mice

Oliveira

Melo

Motta‐Santos

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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We have recently described a new peptide of the renin-angiotensin system, alamandine, a derivative of angiotensin-(1–7). Mas-related G protein-coupled receptor member D (MrgD) was identified as its receptor. Although similar cardioprotective effects of alamandine to those of angiotensin-(1–7) have been described, the significance of this peptide in heart function is still elusive. We aimed to evaluate the functional role of the alamandine receptor MrgD in the heart using MrgD-deficient mice. MrgD was localized in cardiomyocytes by immunofluorescence using confocal microscopy. High-resolution echocardiography was performed in wild-type and MrgD-deficient mice (2 and 12 wk old) under isoflurane anesthesia. Standard B-mode images were obtained in the right and left parasternal long and short axes for morphological and functional assessment and evaluation of cardiac deformation. Additional heart function evaluation was performed using Langendorff isolated heart preparations and inotropic measurements of isolated cardiomyocytes. Immunofluorescence indicated that the MrgD receptor is expressed in cardiomyocytes, mainly in the membrane and perinuclear and nuclear regions. Echocardiography showed left ventricular remodeling and severe dysfunction in MrgD-deficient mice. Strikingly, MrgD-deficient mice presented a pronounced dilated cardiomyopathy with a marked decrease in systolic function. Echocardiographic changes were supported by the data obtained in isolated hearts and inotropic measurements in cardiomyocytes. Our data add new evidence for a major role for alamandine/MrgD in the heart. Furthermore, our results indicate that we have identified a new gene implicated in dilated cardiomyopathy, unveiling a new target for translational approaches aimed to treat heart diseases. NEW & NOTEWORTHY The renin-angiotensin system is a key target for cardiovascular therapy. We have recently identified a new vasodepressor/cardioprotective angiotensin, alamandine. Here, we unmasked a key role for its receptor, Mas-related G protein-coupled receptor member D (MrgD), in heart function. The severe dilated cardiomyopathy observed in MrgD-deficient mice warrants clinical and preclinical studies to unveil its potential use in cardiovascular therapy. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/mrgd-deficiency-leads-to-dilated-cardiomyopathy/ .

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“…The anti-hypertrophic 135 , anti-hypertensive 73 , anti-inflammatory 120 and cardioprotective 6 properties of angiotensin 1-9 have been described. alamandine was discovered in 2013 as an anti-hypertensive agent 67 , and the cardioprotective properties of this compound have since been described 155,156 . NaTure revIewS | CARdiology of ACE2 might have a therapeutic effect, a recombinant human ACE2 (rhACE2) has been developed and tested in animal models.…”

Section: Box 1 | Timeline Of the Discoveries Related To The Counter-rmentioning

confidence: 99%

Counter-regulatory renin–angiotensin system in cardiovascular disease

et al. 2019

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| The renin-angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and IIinitially thought to be biologically inactive -have key roles in cardiovascular physiology and pathophysiology. This non-canonical axis of the renin-angiotensin system consists of angiotensin 1-7 , angiotensin 1-9, angiotensin-converting enzyme 2, the type 2 angiotensin II receptor (AT 2 R), the proto-oncogene Mas receptor and the Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the classical reninangiotensin system. This counter-regulatory renin-angiotensin system has a central role in the pathogenesis and development of various cardiovascular diseases and, therefore, represents a potential therapeutic target. In this Review , we provide the latest insights into the complexity and interplay of the components of the non-canonical renin-angiotensin system, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular disease.

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Alamandine Protects the Heart Against Reperfusion Injury via the MrgD Receptor

Abstract: These results suggest that the cardioprotective effects of alamandine against I/R injury are, in part, related to the activation of antioxidant and antiapoptotic enzymes via the MrgD receptor.

Cited by 22 publications

References 35 publications

Effect of Prolonged Infusion of Alamandine on Cardiovascular Parameters and Cardiac ACE2 Expression in a Rat Model of Renovascular Hypertension

Effect of Prolonged Infusion of Alamandine on Cardiovascular Parameters and Cardiac ACE2 Expression in a Rat Model of Renovascular Hypertension

Genetic deletion of the alamandine receptor MRGD leads to dilated cardiomyopathy in mice

Counter-regulatory renin–angiotensin system in cardiovascular disease

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