Matrix metalloproteinase-2 stimulates collagen-I expression through phosphorylation of focal adhesion kinase in rat cardiac fibroblasts

Hori, Yuichi; Kashimoto, Takeshi; Yonezawa, Tomohiro; Sano, Naoya; Saitoh, Ryuta; Igarashi, Shinya; Chikazawa, Seishiro; Kanai, Kazuaki; Hoshi, Fumio; Itoh, Naoyuki; Higuchi, Seiichi

doi:10.1152/ajpcell.00401.2011

Cited by 30 publications

(25 citation statements)

References 40 publications

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“…To evaluate the degradation of collagen, we assessed the effects of the CSD peptide on expression of three principal matrix metalloproteinase collagenases (MMP-1, MMP-2 and MMP-9), which degrade the extracellular matrix [24], [25]. As shown in Figure 11, the CSD peptide (5 µM) attenuated TGF-β1 induced-decrease of MMPs, whereas the Scr peptide did not significantly affect TGF-β1-mediated changes to MMPs expression levels.…”

Section: Resultsmentioning

confidence: 99%

Role of Caveolin-1 in Atrial Fibrillation as an Anti-Fibrotic Signaling Molecule in Human Atrial Fibroblasts

Liu

Zhong

et al. 2014

PLoS ONE

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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the general population; yet, the precise mechanisms resulting in AF are not fully understood. Caveolin-1 (Cav-1), the principal structural component of caveolae organelles in cardiac fibroblasts, is involved in several cardiovascular conditions; however, the study on its function in atrium, in particular, in AF, is still lacking. This report examines the hypothesis that Cav-1 confers an anti-AF effect by mediating atrial structural remodeling through its anti-fibrotic action. We evaluated the expression of Cav-1, transforming growth factor-β1 (TGF-β1), and fibrosis in atrial specimens of 13 patients with AF and 10 subjects with sinus rhythm, and found that the expression of Cav-1 was significantly downregulated, whereas TGF-β1 level, collagens I/III contents and atrial fibrosis were markedly increased, in AF. Western blot analysis demonstrated that treatment of human atrial fibroblasts (HAFs) with TGF-β1 resulted in a concentration- and time-dependent repression of Cav-1. Downregulation of Cav-1 with siRNA increased the TGF-β1-induced activation of Smad signal pathway and collagens production in HAFs. Furthermore, incubation of HAFs with the peptides derived from Cav-1 to achieve Cav-1 gain-of-function abolished the TGF-β1-induced production of collagens I/III and decreases of MMP-2/-9 expression. Therefore it was concluded that Cav-1 is an important anti-AF signaling mediator by conferring its anti-fibrotic effects in atrium.

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Section: Resultsmentioning

confidence: 99%

Role of Caveolin-1 in Atrial Fibrillation as an Anti-Fibrotic Signaling Molecule in Human Atrial Fibroblasts

Liu

Zhong

et al. 2014

PLoS ONE

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“…Although MMPs degrade ECM components, excessive MMP activation is concomitant with cardiac fibrosis in the rat diabetic myocardium [36]. Conversely, inhibition of MMP activity was reported to prevent LV remodelling in a rabbit model [37]. Recently, irisin was shown to promote MMP up-regulation in HUVECs [38].…”

Section: Discussionmentioning

confidence: 99%

Irisin inhibits high glucose‐induced endothelial‐to‐mesenchymal transition and exerts a dose‐dependent bidirectional effect on diabetic cardiomyopathy

Mujahid

Rong

et al. 2017

J Cellular Molecular Medi

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Emerging evidence indicates that irisin provides beneficial effects in diabetes. However, whether irisin influences the development of diabetic cardiomyopathy (DCM) remains unclear. Therefore, we investigated the potential role and mechanism of action of irisin in diabetes‐induced myocardial dysfunction in mice. Type 1 diabetes was induced in mice by injecting streptozotocin, and the diabetic mice were administered recombinant r‐irisin (low or high dose: 0.5 or 1.5 μg/g body weight/day, I.P.) or PBS for 16 weeks. Irisin treatment did not alter blood glucose levels in the diabetic mice. However, the results of echocardiographical and histopathological assays indicated that low‐dose irisin treatment alleviated cardiac fibrosis and left ventricular function in the diabetic mice, whereas high‐dose irisin failed to mitigate the ventricular function impairment and increased collagen deposition. The potential mechanism underlying the effect of low‐dose irisin involved irisin‐mediated inhibition of high glucose‐induced endothelial‐to‐mesenchymal transition (EndMT); conversely, high‐dose irisin treatment enhanced high glucose‐induced MMP expression by stimulating MAPK (p38 and ERK) signalling and cardiac fibroblast proliferation and migration. Low‐dose irisin alleviated DCM development by inhibiting high glucose‐induced EndMT. By contrast, high‐dose irisin disrupted normal MMP expression and induced cardiac fibroblast proliferation and migration, which results in excess collagen deposition. Thus, irisin can inhibit high glucose‐induced EndMT and exert a dose‐dependent bidirectional effect on DCM.

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“…While increased proteolytic activity may contribute to degradation of myofilaments in acute cardiac conditions [35][36][37], chronic increases in this activity are associated with enhanced extracellular matrix deposition. This leads to hypertrophy likely because excessive MMP-2 activates pro-fibrotic intracellular pathways that increase collagen-I synthesis by cardiac fibroblasts [38].…”

Section: Discussionmentioning

confidence: 99%

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

Cau

Guimaraes

Rizzi

et al. 2015

Basic Clin Pharma Tox

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Imbalanced matrix metalloproteinase (MMP) activity is involved in hypertensive cardiac hypertrophy. Pharmacological inhibition of nuclear factor kappaB (NF-кB) with pyrrolidine dithiocarbamate (PDTC) can prevent MMP up-regulation. We suggested that treatment with PDTC could prevent 2-kidney, 1-clip (2K1C) hypertension-induced left ventricular remodelling. Sham-operated controls or 2K1C rats with hypertension received either vehicle or PDTC (100 mg/kg/day) by gavage for 8 weeks. Systolic blood pressure was monitored every week. Histological assessment of left ventricles was carried out with haematoxylin/eosin sections, and fibrosis was quantified in picrosirius red-stained sections. Oxidative stress was evaluated in heart samples with the dihydroethidium probe. Cardiac MMP activity was determined by in situ zymography, and cardiac MMP-2 was assessed by immunofluorescence. 2K1C surgery significantly increased systolic blood pressure in the 2K1C vehicle. PDTC exerted antihypertensive effects after 2 weeks of treatment. Histology revealed increased left ventricular and septum wall thickness associated with augmented myocyte diameter in hypertensive rats, which were reversed by treatment with PDTC. Hypertensive rats developed pronounced cardiac fibrosis with increased interstitial collagen area, increased cardiac reactive oxygen species levels, gelatinase activity and MMP-2 expression. PDTC treatment decreased these alterations. These findings show that PDTC modulates myocardial MMP-2 expression and ameliorates cardiac remodelling in renovascular hypertension. These results suggest that interfering with MMP expression at transcriptional level may be an interesting strategy in the therapy of organ damage associated with hypertension.It is well known that cardiac hypertrophy develops in response to many pathophysiological stimuli, particularly to pressure/volume overload and neurohormonal activation [1]. Although hypertension-associated cardiac remodelling is an initial adaptive process, sustained remodelling ultimately leads to progressive heart failure and death [1][2][3]. Common morphological features in hypertension-associated left ventricular remodelling include enlargement of cardiomyocytes and stimulated collagen turnover, resulting in net accumulation of interstitial collagen in cardiovascular tissues [3,4].Due to their fundamental role in extracellular matrix turnover and reorganization, matrix metalloproteinases (MMP), a so-called group of metalloenzymes, has been implicated as mediators of cardiac hypertrophy [5,6]. MMPs are proteases dependent on zinc and calcium and cleave several components of the extracellular matrix such as collagen, promoting the remodelling of tissue architecture and cell growth under both physiological and pathological conditions [7]. Additionally, MMP-2 degrades intracellular proteins such as troponin-I [8], myosin light chain [9], a-actinin [10] and titin [11], thus contributing to cardiac dysfunction. Transgenic mice with increased MMP-2 expression in cardiomyocytes deve...

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Matrix metalloproteinase-2 stimulates collagen-I expression through phosphorylation of focal adhesion kinase in rat cardiac fibroblasts

Cited by 30 publications

References 40 publications

Role of Caveolin-1 in Atrial Fibrillation as an Anti-Fibrotic Signaling Molecule in Human Atrial Fibroblasts

Role of Caveolin-1 in Atrial Fibrillation as an Anti-Fibrotic Signaling Molecule in Human Atrial Fibroblasts

Irisin inhibits high glucose‐induced endothelial‐to‐mesenchymal transition and exerts a dose‐dependent bidirectional effect on diabetic cardiomyopathy

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

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