Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure

Abstract

Extracellular matrix (ECM) turnover is regulated by matrix metalloproteinases (MMPs) and plays an important role in cardiac remodeling. Previous studies from our lab demonstrated an increase in gelatinolytic‐MMP‐2 and ‐9 activities in endocardial tissue from ischemic cardiomyopathic (ICM) and idiopathic dilated cardiomyopathic (DCM) hearts. The signaling mechanism responsible for the left ventricular (LV) remodeling, however, is unclear. Administration of cardiac specific inhibitor of metalloproteinase (CIMP) prevented the activation of MMP‐2 and ‐9 in ailing to failing myocardium. Activation of MMP‐2 and ‐9 leads to induction of proteinase activated receptor‐1 (PAR‐1). We hypothesize that the early induction of MMP‐9 is a key regulator for modulating intracellular signaling through activation of PAR and various downstream events which are implicated in development of cardiac fibrosis in an extracellular receptor mediated kinase‐1 (ERK‐1) and focal adhesion kinase (FAK) dependent manner. To test this hypothesis, explanted human heart tissues from ICM and DCM patients were obtained at the time of orthotopic cardiac transplants. Quantitative analysis of MMP‐2 and ‐9 gelatinolytic activities was made by real‐time quantitative zymography. Gel phosphorylation staining for PAR‐1 showed a significant increase in ICM hearts. Western blot and RT‐PCR analysis and in‐situ labeling, showed significant increased expression of PAR‐1, ERK‐1and FAK in ICM and DCM. These observations suggest that the enhanced expression and potentially increased activity of LV myocardial MMP‐9 triggers the signal cascade instigating cardiac remodeling. This early mechanism for the initiation of LV remodeling appears to have a role in end‐stage human heart failure.

Involvement of Protein Kinase C and RhoA in Protease-Activated Receptor 1–Mediated F-Actin Reorganization and Cell Growth in Rat Cardiomyocytes

“…An increase in the expression of this receptor has been found in the hearts of patients with ischemic and idiopathic dilated cardiomyopathy (6) and in the left ventricle of a mouse model of chronic heart failure (7). There is now substantial evidence that PAR1 stimulation modulates several cardiac cell functions, for example, an increase in contractility and the occurrence of arrhythmia (8,9).…”

H2S ameliorates oxidative and proteolytic stresses and protects the heart against adverse remodeling in chronic heart failure

“…MMPs are a family of structurally and functionally related zinc-dependent endoproteinases that play a pivotal role in ECM remodeling through its proteolytic effect (19). MMP-2 and MMP-9 have collagen binding fibronectin type II inserts in their catalytic domain, making those indispensible for ECM remodeling in the heart, where elastin-to-collagen ratio determines the extent of cardiac dysfunction in chronic heart failure (CHF) (13). MMPs are in a latent state in the heart, maintaining normal elastin-to-collagen ratio through matrix synthesis and degradation.…”

Plasma heparin cofactor II activity is inversely associated with left atrial volume and diastolic dysfunction in humans with cardiovascular risk factors

“…36 PAR-1 expression is increased in the LV of a mouse model for chronic HF 37 and Pawlinski et al 38 demonstrated that PAR-1 overexpression by cardiomyocytes induced cardiac hypertrophy in MHC-PAR-1 mice. These hypertrophic changes of cardiomyocytes by PAR-1 activation may be partly explained by the mechanism of cleavage of PAR-1 resulting in activation of Gq, G12/ 13 and Gi, as well as downstream signaling pathways, including the MAPK pathways ERK 1/2 and ERK5.…”