(Pro)renin receptor expression in myocardial infarction in transgenic mice expressing rat tonin

Ribeiro, Amanda Aparecida; Amorim, Rebeca Padrão; Palomino, Zaira; Lima, Matheus Thomaz Nogueira Silva; Moraes‐Silva, Ivana C.; Souza, Leandro Franco de; Pesquero, Jorge Luiz; Irigoyen, Maria Cláudia; Casarini, Dulce Elena

doi:10.1016/j.ijbiomac.2017.10.179

Cited by 9 publications

(5 citation statements)

References 35 publications

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“…PRR is a single trans-membrane protein that binds both renin and prorenin, and has been implicated in a number of cardiovascular diseases (6,7). Binding of ligand to PRR leads to renin activation and non-proteolytic activation of prorenin, the formation of angiotensin II (AngII), and the activation of a variety of AngII-independent signal transduction pathways, such as the mitogen-activated protein kinase (MAPK) signaling pathway (8).…”

Section: Introductionmentioning

confidence: 99%

(Pro)renin receptor-mediated myocardial injury, apoptosis, and inflammatory response in rats with diabetic cardiomyopathy

Xia

Wang

et al. 2019

Journal of Biological Chemistry

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Excessive activation of the renin-angiotensin system (RAS) in diabetic cardiomyopathy (DCM) provokes a series of structural and functional abnormalities, and causes ventricular remodeling and heart failure in diabetes. (Pro)renin receptor (PRR) is a component of the RAS and has been reported to be up-regulated in some cardiovascular diseases. Furthermore, PRR blockade in some cardiovascular diseases, such as myocardial infarction and hypertension, has been demonstrated to reverse their pathogenesis. However, there have been few studies about the function of PRR in the pathogenesis of DCM. In this study, we hypothesized that PRR is involved in the pathogenesis of DCM and mediates myocardial injury in DCM. To explore the role of PRR in DCM, we evaluated the effects of PRR overexpression and knockdown on the DCM phenotype in vivo and in vitro. The results show that PRR overexpression exacerbates myocardial injury and the inflammatory response in rats with DCM. Conversely, PRR knockdown alleviates myocardial fibrosis, apoptosis, and the inflammatory response, reversing the cardiac dysfunction in rats with DCM. In cell experiments, PRR overexpression also up-regulated the protein expression of collagen I and fibronectin, aggravated the inflammatory response, and increased the production of reactive oxygen species (ROS), while PRR knockdown had the opposite effect.

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Section: Introductionmentioning

confidence: 99%

(Pro)renin receptor-mediated myocardial injury, apoptosis, and inflammatory response in rats with diabetic cardiomyopathy

Xia

Wang

et al. 2019

Journal of Biological Chemistry

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“…Sensitization of AT1R could be one of the mechanisms to increase responsiveness of AT1R. Surprisingly, the Ang II levels in the TGM'(rTon) heart were lower compared to the WT group, even though increased tonin activity was observed in the atria and left ventricle as we previously described (18). The lower Ang II levels could be the result of changes in the dynamics of the renin-angiotensin system kinetics, favoring the formation of Ang 1-7 from Ang II.…”

Section: Discussionmentioning

confidence: 49%

“…Transgenic TGM'(rTon) mice were generated by microinjection of the rat tonin transgene into zygotes as described by Ribeiro et al (17, 18). TGM'(rTon) mice exhibited higher tonin activity in the brain, heart, kidney, liver, and bladder compared to WT (17).…”

Section: Methodsmentioning

confidence: 99%

Tonin Overexpression in Mice Diminishes Sympathetic Autonomic Modulation and Alters Angiotensin Type 1 Receptor Response

et al. 2019

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Background: Tonin, a serine-protease that forms Angiotensin II (AngII) from angiotensinogen, is increased in failing human heart samples. Increased blood pressure (BP) and decreased heart rate (HR) variabilities are associated with higher risk of cardiovascular morbidity. Losartan has been used to reduce hypertension and, therefore, lowers the risk of fatal and non-fatal cardiovascular events. Determination of tonin's impact on BP and HR variabilities as well as the impact of losartan remain questions to be elucidated.Aim: Evaluation of cardiovascular autonomic profile in transgenic mice overexpressing the rat tonin enzyme TGM'(rton) and the impact of AT1 receptor blocker, losartan.Methods: Male C57BL/6 (WT) and TGM'(rTon) mice were cannulated for recording BP (Windaq, 4 MHz) for 30 min at baseline and 30 min after losartan injection (20 mg/kg). BP and HR variabilities were analyzed in time and frequency domain method. Low-frequency (LF) and high-frequency (HF) components were identified for sympathetic and parasympathetic modulations analysis. Ang I, AngII, and Ang1-7 were quantified by high performance liquid chromatography method. The total enzymatic activity for AngI, AngII, and Ang1-7 formation was evaluated in the heart and plasma by Liquid chromatography mass spectrometry (LC-MS/MS).Results: At the baseline TGM'(rTon) exhibited higher BP, lower cardiac LF, higher cardiac HF, lower LF/HF, and lower alpha index than wild type (WT). After losartan injection, TGM'(rTon) mice presented an additional decrease in cardiac LF and increase in HF in relation to baseline and WT. In the vasculature, losartan caused decreased in BP and LF of systolic BP in WT mice in relation to its baseline. A similar effect was observed in the BP of TGM'(rTon) mice; however, LF of systolic BP increased compared to baseline. Our data also indicates that AT1R receptor signaling has been altered in TGM’(rTon)mice. Interestingly, the dynamics of the renin-angiotensin system kinetics change, favoring production of Ang1-7.Conclusion: Autonomic evaluation of TGM’(rTon) mice indicates an unclear prognosis for diseases that affect the heart. HR variability in TGM’(rTon) mice indicates high risk of morbidity, and sympathetic and parasympathetic modulation indicate low risk of morbidity. The low risk of morbidity could be the biased production of Ang1-7 in the heart and circulation; however, the altered response of AT1R in the TGM’(rTon) remains to be elucidated, as well aswhether that signaling is pro-protection or pro-pathology.

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“…32 Therefore, these results indicate that increased myocardial PRR expression plays a significant role in the pathological progression of atrial fibrillation and triggers cardiac remodeling in a normal heart but not in a stressed heart. Although PRR expression in the atrium and right ventricle of mice with myocardial infarction trended to increase with no statistical significance, 33 the PRR antagonist HRP (Handle region peptide, I 10 PLKKMPS 19 ) ameliorated cardiac fibrosis/hypertrophy, infarct size, and cardiac dysfunction F I G U R E 1 An overview of biological effects of (Pro)renin receptor (PRR) and its downstream signals in heart diseases. MAPK, mitogenactivated protein kinase; NOX 4 , NADPH oxidase 4; pERK1/2, phosphorylated extracellular signal-regulated kinase 1/2; PKC, protein kinase C; PLC-β3, phospholipase C-β3; Raf-1, rapidly accelerated fibrosarcoma-1; RAS, renin-angiotensin system; ROS, reactive oxygen species; YAP, yes-associated protein…”

Section: Activation Of Cardiac Prr Results In Cardiac Hypertrophymentioning

confidence: 99%

“…Therefore, these results indicate that increased myocardial PRR expression plays a significant role in the pathological progression of atrial fibrillation and triggers cardiac remodeling in a normal heart but not in a stressed heart. Although PRR expression in the atrium and right ventricle of mice with myocardial infarction trended to increase with no statistical significance, 33 the PRR antagonist HRP (Handle region peptide, I 10 PLKKMPS 19 ) ameliorated cardiac fibrosis/hypertrophy, infarct size, and cardiac dysfunction after myocardial infarction 34 . Overall, PRR may be a novel therapeutic target for cardiac remodeling.…”

Section: Pathophysiological Functions Of the Cardiac Prrmentioning

confidence: 99%

Cardiovascular aspects of the (pro)renin receptor: Function and significance

Liu

Xiong

2022

The FASEB Journal

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Cardiovascular diseases (CVDs), including all types of disorders related to the heart or blood vessels, are the major public health problems and the leading causes of mortality globally. (Pro)renin receptor (PRR), a single transmembrane protein, is present in cardiomyocytes, vascular smooth muscle cells, and endothelial cells. PRR plays an essential role in cardiovascular homeostasis by regulating the renin‐angiotensin system and several intracellular signals such as mitogen‐activated protein kinase signaling and wnt/β‐catenin signaling in various cardiovascular cells. This review discusses the current evidence for the pathophysiological roles of the cardiac and vascular PRR. Activation of PRR in cardiomyocytes may contribute to myocardial ischemia/reperfusion injury, cardiac hypertrophy, diabetic or alcoholic cardiomyopathy, salt‐induced heart damage, and heart failure. Activation of PRR promotes vascular smooth muscle cell proliferation, endothelial cell dysfunction, neovascularization, and the progress of vascular diseases. In addition, phenotypes of animals transgenic for PRR and the hypertensive actions of PRR in the brain and kidney and the soluble PRR are also discussed. Targeting PRR in local tissues may offer benefits for patients with CVDs, including heart injury, atherosclerosis, and hypertension.

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(Pro)renin receptor expression in myocardial infarction in transgenic mice expressing rat tonin

Cited by 9 publications

References 35 publications

(Pro)renin receptor-mediated myocardial injury, apoptosis, and inflammatory response in rats with diabetic cardiomyopathy

(Pro)renin receptor-mediated myocardial injury, apoptosis, and inflammatory response in rats with diabetic cardiomyopathy

Tonin Overexpression in Mice Diminishes Sympathetic Autonomic Modulation and Alters Angiotensin Type 1 Receptor Response

Cardiovascular aspects of the (pro)renin receptor: Function and significance

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