Matrix metalloproteinase 3 regulates angiotensin II-induced myocardial fibrosis cell viability, migration and apoptosis

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Abstract

Angiotensin II (AngII) is a central signaling molecule of the renin-angiotensin system that serves a vital role in myocardial fibrosis (MF). The present study aimed to investigate the effects of matrix metalloproteinase (MMP)3 on MF progression. To induce cellular fibrosis, H9C2 rat myocardial cells were treated with AngII for 24 h. Subsequently, cells were treated with levocarnitine, or transfected with small interfering (si)RNA-negative control or siRNA-MMP3 (1/2/3). Cell viability, apoptosis and migration were assessed by performing Cell Counting Kit-8, flow cytometry and Transwell assays, respectively. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were performed to determine the expression levels of MF biomarkers, including disease-, apoptosis- and oxidative stress-related genes. Compared with the control group, AngII significantly inhibited H9C2 cell viability and migration, and significantly increased H9C2 cell apoptosis (P<0.05). However, compared with AngII-treated H9C2 cells, MMP3 knockdown significantly inhibited fibrotic H9C2 cell viability and migration, but increased fibrotic H9C2 cell apoptosis (P<0.05). The RT-qPCR results demonstrated that MMP3 knockdown significantly downregulated the expression levels of AXL receptor tyrosine kinase, AngII receptor type 1, α-smooth muscle actin and Collagen I in AngII-treated H9C2 cells (P<0.05). Moreover, compared with AngII-treated cells, MMP3 knockdown significantly decreased Bcl-2 expression levels, but significantly increased caspase-3 and p53 expression levels in AngII-treated cells (P<0.05). Additionally, compared with AngII-treated cells, MMP3 knockdown significantly decreased MMP3, MMP9, STAT3, p22Phox and p47Phox expression levels in AngII-treated cells (P<0.05). The present study indicated that MMP3 knockdown altered myocardial fibroblast cell viability, migration and apoptosis by regulating apoptosis- and oxidative stress-related genes, thus delaying MF progression.

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The pathogenesis of cardiac fibrosis.

Ping Kong, Panagiota Christia, Nikolaos G Frangogiannis (2014)

Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.

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Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure.

Vaibhav B Patel, Jiu-Chang Zhong, Maria B. Grant … (2016)

Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.

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Oxidative stress and heart failure.

Shouji Matsushima, Shintaro Kinugawa, Hiroyuki Tsutsui (2011)

Oxidative stress, defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defense, has been shown to play an important role in the pathophysiology of cardiac remodeling and heart failure (HF). It induces subtle changes in intracellular pathways, redox signaling, at lower levels, but causes cellular dysfunction and damage at higher levels. ROS are derived from several intracellular sources, including mitochondria, NAD(P)H oxidase, xanthine oxidase, and uncoupled nitric oxide synthase. The production of ROS is increased within the mitochondria from failing hearts, whereas normal antioxidant enzyme activities are preserved. Chronic increases in ROS production in the mitochondria lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further ROS generation, and cellular injury. ROS directly impair contractile function by modifying proteins central to excitation-contraction coupling. Moreover, ROS activate a broad variety of hypertrophy signaling kinases and transcription factors and mediate apoptosis. They also stimulate cardiac fibroblast proliferation and activate the matrix metalloproteinases, leading to the extracellular matrix remodeling. These cellular events are involved in the development and progression of maladaptive myocardial remodeling and failure. Oxidative stress is also involved in the skeletal muscle dysfunction, which may be associated with exercise intolerance and insulin resistance in HF. Therefore, oxidative stress is involved in the pathophysiology of HF in the heart as well as in the skeletal muscle. A better understanding of these mechanisms may enable the development of novel and effective therapeutic strategies against HF.

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Author and article information

Journal

Journal ID (nlm-ta): Mol Med Rep

Journal ID (iso-abbrev): Mol Med Rep

Title: Molecular Medicine Reports

Publisher: D.A. Spandidos

ISSN (Print): 1791-2997

ISSN (Electronic): 1791-3004

Publication date (Print): February 2021

Publication date (Electronic): 20 December 2020

Publication date PMC-release: 20 December 2020

Volume: 23

Issue: 2

Electronic Location Identifier: 151

Affiliations

[1 ]Department of Gerontology, Shibei Hospital of Jing'an District, Shanghai 200443, P.R. China

[2 ]Department of Gerontology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, P.R. China

Author notes

Correspondence to: Professor Li Jin, Department of Gerontology, Shibei Hospital of Jing'an District, 4500 Gonghe Xin Road, Jing'an, Shanghai 200443, P.R. China, E-mail: jinli923@ 123456126.com

Professor Haiya Wang, Department of Gerontology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Manufacturing Bureau Road, Huangpu, Shanghai 200011, P.R. China, E-mail: whyrenji@ 123456163.com

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Article

Publisher ID: MMR-0-0-11790

DOI: 10.3892/mmr.2020.11790

PMC ID: 7789094

PubMed ID: 33655326

SO-VID: a16e632f-c440-44e3-95b3-7d0b84c5765b

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 02 July 2020

Date accepted : 23 November 2020

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Matrix metalloproteinase 3 regulates angiotensin II-induced myocardial fibrosis cell viability, migration and apoptosis

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Numerical Algebra, Matrix Theory, Differential-Algebraic Equations, and Control Theory

Most cited references 56

The pathogenesis of cardiac fibrosis.

Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure.

Oxidative stress and heart failure.

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