Transgenic MMP-2 expression induces latent cardiac mitochondrial dysfunction

Abstract

Matrix metalloproteinases (MMPs) are central to the development and progression of dysfunctional ventricular remodeling after tissue injury. We studied 6 month old heterozygous mice with cardiac-specific transgenic expression of active MMP-2 (MMP-2 Tg). MMP-2 Tg hearts showed no substantial gross alteration of cardiac phenotype compared to age-matched wild-type littermates. However, buffer perfused MMP-2 Tg hearts subjected to 30 min of global ischemia followed by 30 min of reperfusion had a larger infarct size and greater depression in contractile performance compared to wild-type hearts. Importantly, cardioprotection mediated by ischemic preconditioning (IPC) was completely abolished in MMP-2 Tg hearts, as shown by abnormalities in mitochondrial ultrastructure and impaired respiration, increased lipid peroxidation, cell necrosis and persistently reduced recovery of contractile performance during post-ischemic reperfusion. We conclude that MMP-2 functions not only as a proteolytic enzyme but also as a previously unrecognized active negative regulator of mitochondrial function during superimposed oxidative stress.

Mitochondrial matrix metalloproteinase activation decreases myocyte contractility in hyperhomocysteinemia

“…A recent study suggested that the overexpression of MMP-2 causes mitochondrial dysfunction by degrading the mitochondrial membrane potential (36). HHCY is well associated with the mitochondrial abnormalities.…”

“…Although there is little information regarding the mechanisms by which MMP-2 disrupts mitochondria, it is well-recognized that reactive oxygen species generated by mitochondria can drive both MMP-2 expression and activation (25). Such activation could result in a negative feedback mechanism that degrades mitochondrial membrane potential and impairs mitochondrial function (36). We have shown that HCY-induced calpain protease activation induces mitochondrial permeability transition (MPT), and the treatment with NMDA-R1 blocker MK-801 attenuates HCYinduced MPT in HL-1 cardiomyocytes (23).…”

Restoration of contractility in hyperhomocysteinemia by cardiac-specific deletion of NMDA-R1

“…Others and we have shown the presence of MMP in the mitochondria (mtMMP) (10,11,15). The abnormal activation of MMP impairs the mitochondrial function (25). Very recently, by using a pharmacological blocker for NMDA-R1, our laboratory has suggested that HCY agonizes NMDA-R1 and causes a decline in myocyte contractility, in part, by inducing MMP-9 in the mitochondria (16).…”

Association of matrix metalloproteinase-2 gene promoter polymorphism with myocardial infarction susceptibility in a Mexican population

“…This enzyme is elevated in atherosclerotic plaques of coronary arteries (Pasterkamp et al 2000) as well as in plasma after the onset of AMI (Hojo et al 2001). Additionally, mice with cardiac-specific transgenic expression of active MMP-2 have a larger infarction size compared to wild-type hearts (Zhou et al 2007). MMP-2 -1306CC genotype increases MMP-2 expression in vitro and this increase could be related to AMI through two processes: (i) by facilitating leukocyte and lipoprotein infiltration into the endothelium, which is necessary for the development of atherosclerosis, and (ii) by weakening the arterial wall, which can destabilize and break atheromatous plaque, leading to AMI (Newby 2005;Tedgui and Mallat 2006).…”