The Dynamic Interaction Between Matrix Metalloproteinase Activity and Adverse Myocardial Remodeling

Abstract

The process of cardiac remodeling in response to cardiac injury and/or persistent elevations in wall stress generally relates to the progressive changes that occur in ventricular chamber dimensions and the various components of the myocardium, in particular the cardiomyocytes and the extracellular matrix. Volume overload, pressure overload or myocardial injury produces a sustained abnormal elevation in myocardial wall stress which initiates cardiac remodeling that frequently results in ventricular decompensation and heart failure. Regardless of the inciting cause, there appear to be three distinct phases to this process. In the initial phase, fibrillar collagen is partially degraded secondary to increased matrix metalloproteinase (MMP) activity. Following this, there is a chronic compensatory phase during which MMP activity and collagen concentration return to normal while cardiomyocyte size continues to progressively increase. The final phase is attained once the compensatory hypertrophic mechanisms are exhausted and is characterized by elevated MMP activity, marked ventricular dilatation and prominent fibrosis. Details of this progressive, dynamic remodeling process and its effect on ventricular function during chronic volume overload, chronic pressure overload and following myocardial infarction will be the focus of this article.

Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients

“…12 In cardiac hypertrophy, it has been shown that the overall MMP gelatinolytic activity is increased and has crucial roles in the development of LVH and in the progression to decompensated LVH and heart failure. 6,7,28 Although our results suggesting a protective role for a MMP-2 polymorphism and haplotype associated with higher MMP-2 expression may seem paradoxical, little is known about the specific role for each MMP in this process and the possible signalling pathways that depend on them. 29 In this respect, transgenic models have contributed to the understanding of the roles for MMPs in LVH, and MMP-2 knockout mice present interesting reductions in LVH and its complications in models of heart hypertrophy.…”

“…6,7,9 Given the relevance of MMP-2 in these processes, functional genetic polymorphisms of this gene may affect the prevalence of LVH in hypertensive patients. This is the first report to show a protective effect associated with the CC genotype of the C À1306 T polymorphism against increases in EDD and LVMI in hypertensive subjects.…”

“…Several MMPs are upregulated in cardiac hypertrophy and an imbalance between MMPs and their endogenous inhibitors (tissue inhibitor of metalloproteinases-TIMPs) may underlie the transition of compensated LVH to dilated LVH. [3][4][5][6][7] In addition, experimental evidence suggests that nonspecific inhibition of MMPs, especially MMP-2, ameliorates hypertensive cardiovascular remodelling. 8 MMPs activities are regulated at different levels including transcription, activation of latent forms of MMPs and inhibition by TIMPs 5,9 In this respect, genetic polymorphisms in MMP-2 gene may also affect MMP-2 expression or activity, as shown in several disease conditions.…”

Sex differences in myocardial infarction and rupture

“…Disruption of the collagen matrix by increased MMP activity leads to increased stress for the cardiomyocytes, and therefore leads to further hypertrophy and remodeling [24]. In addition, this dissociation of collagen bundles by MMPs simulates further collagen synthesis through transcriptional activation of the corresponding genes [24]. The role of collagen in the resistance of the ventricular wall against rupture is further supported by the observation that transgenic mice with cardiac over-expression of the β 2 -adrenergic receptor have a lower rate of rupture compared to wild type mice, which correlates with a higher accumulation of interstitial collagen in the transgenic animal [25].…”

“…Among the multiple forms of MMPs, the gelatinases MMP2 and MMP9 are expressed both in cardiac fibroblasts and in myocytes, and can degrade several types of collagen (including the types 1 and 3) [23]. Disruption of the collagen matrix by increased MMP activity leads to increased stress for the cardiomyocytes, and therefore leads to further hypertrophy and remodeling [24]. In addition, this dissociation of collagen bundles by MMPs simulates further collagen synthesis through transcriptional activation of the corresponding genes [24].…”