Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling

Abstract

Myocardial fibrosis due to maladaptive extracellular matrix remodeling contributes to dysfunction of the failing heart. Further elucidation of the mechanism by which myocardial fibrosis and dilatation can be prevented or even reversed remains of great interest as a potential means to limit myocardial remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving force behind extracellular matrix degradation during remodeling and are increased in the failing human heart. MMPs are regulated by a variety of growth factors, cytokines, and matrix fragments such as matrikines. In the present report, we discuss the regulation of MMPs, the role of MMPs in the development of cardiac fibrosis, and the modulation of MMP activity using gene transfer and knockout technologies. We also present recent findings from our laboratory on the regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming growth factor-beta(1) in the failing human heart before and after left ventricular assist device support, as well as the possibility of preventing ventricular fibrosis using different anti-MMP strategies. Several studies suggest that such modulation of MMP activity can alter ventricular remodeling, myocardial dysfunction, and the progression of heart failure. It is therefore suggested that the interplay of MMPs and their regulators is important in the development of the heart failure phenotype, and myocardial fibrosis in heart failure may be modified by modulating MMP activity.

Effects of Pressure Overload on Extracellular Matrix Expression in the Heart of the Atrial Natriuretic Peptide–Null Mouse

“…Increased cardiac ECM deposition is due to a combination of increased biosynthesis and decreased degradation of ECM proteins, likely related to reduced MMP activity. [21][22][23] MMPs are tightly regulated at several levels, including transcription, secretion, and conversion of the zymogen to the active protease, in part through the action of endogenous protease inhibitors (TIMPs). 23,24 Altered expression and activity of various MMPs and TIMPs have been detected during cardiac remodeling induced by a variety of stimuli.…”

“…[21][22][23] MMPs are tightly regulated at several levels, including transcription, secretion, and conversion of the zymogen to the active protease, in part through the action of endogenous protease inhibitors (TIMPs). 23,24 Altered expression and activity of various MMPs and TIMPs have been detected during cardiac remodeling induced by a variety of stimuli. [21][22][23]25 More specifically, expression of MMP-1, -2, -9, and -13 and of TIMP-1, -2, and -4 have been correlated with the development of cardiac hypertrophy and failure in rodent heart.…”

Effect of Novel Gasotransmitter hydrogen sulfide on renal fibrosis and connexins expression in diabetic rats

“…3 The disorder of matrix metalloproteinases and the tissue inhibitors of metalloproteinases (MMPS/TIMPs) have relation with nephropathy fibrosis. 4 Studies show that gap junction plays a significant role in ischemic renal injury and the occurrence and development of DN, and Cx43, Cx40 and Cx45 are the main connexins expressed in the kidney. It has been found that constantly lowering Cx43 expression in cells after tissue injury may lead to changes of intercellular junction and intracellular space, thus causing the pathophysiological changes of DN.…”

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

“…Of note, Feldman and colleagues have suggested the interesting possibility that MMP induced degradation products, or "matrikines," are responsible for the progressive tissue fibrosis in their model of sustained TNF overexpression. 6,7 A second possible explanation for the increased fibrosis observed in the TNF transgenic mice is that TNF mediated signaling increases the density of angiotensin type I receptors (AT 1 ) on cardiac fibroblasts, 8 and that this increase in AT 1 receptor density sensitizes cardiac fibroblasts to the profibrotic actions of endogenous angiotensin II. 5 Germane to the present discussion, we have shown that both transforming growth factor-β 1 (TGF-β 1 ) and TGF-β 2 mRNA and protein levels are significantly increased in the hearts of the MHCsTNF transgenic mice relative to littermate controls, raising the interesting possibility that TGF-β mediated signaling was responsible for the fibrosis observed in the MHCsTNF mice.…”