Matrix metalloproteinase-2 and myocardial oxidative stress injury: beyond the matrix

Abstract

Matrix metalloproteinase (MMP)-2 belongs to a family of zinc-dependent proteases which are best known for their ability to proteolyse extracellular matrix proteins throughout the body, including the cardiovascular system. Increased MMP-2 activity has been demonstrated in myocardial ischaemia and reperfusion injury and the progression to congestive heart failure, with most evidence to date for its role in cardiac remodelling. Recent evidence, however, shows that MMP-2 also co-localizes with and proteolyses specific protein targets within the cardiomyocyte to cause acute, reversible contractile dysfunction, challenging the conventional wisdom on the 'extracellular matrix only' actions of this enzyme. In this review, we discuss the recent upsurge in MMP-2 research with regards to its activation by non-proteolytic pathways in the setting of enhanced oxidative stress in the heart. We will focus on the consequences of intracellular actions of MMP-2 within the cardiomyocyte and its regulation at several levels including its expression, post-translational modifications, and regulation by endogenous tissue inhibitors of metalloproteinases, caveolin, and small molecule MMP inhibitors. MMP-2 is emerging as an important signalling protease implicated in the proteolytic regulation of various intracellular proteins in myocardial oxidative stress injury.

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

“…32 It is also relevant to mention that many other actions independent of matrix degradation have been attributed to MMPs, especially MMP-2, and these actions may be very relevant to cardiac remodelling. 29,33,34 Although we do not have a mechanistic explanation for the associations being reported here, it is clear that complex interactions of factors regulate MMPs activities in the heart. The present study has some limitations.…”

“…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. 30 These mice have increased TIMP-4 levels in the heart, and TIMP-4 is a major MMPs inhibitor.…”

Gelatinases and their tissue inhibitors in a group of subjects with obstructive sleep apnea syndrome

“…Gelatinases A and B (MMP-2 and -9) are responsible for IV type collagen, gelatin and laminin degradation, vasculature remodeling, angiogenesis, inflammation and then they are involved in the atherosclerotic process [10,24]. Once they are secreted in the extracellular space, MMPs may be activated by several proteases, other MMPs, and ROS, in particular peroxynitrite [1,15,16]. Some authors have described an overexpression of MMP-9 in older atherosclerotic lesions [20], responsible for a large remodeling characterized by fibrosis, matrix degradation and angiogenesis, resulting in plaque instability and rupture [11,20].…”

Concentrações de MMP-8, MMP-9, MPO, TIMP-1 e TIMP-2 na saliva e correlações com plasma

“…Eles possuem seis pontes de dissulfeto cada, responsáveis pela manutenção de sua estrutura terciária (Kandasamy, Chow et al 2009). …”

“…Além disso, o TIMP-1 não possui ação inibitória sobre as MT-MMPs (Kandasamy, Chow et al 2009), e o TIMP-2 não interagem com a MMP-9 (Vanhoutte and Heymans 2010 Além disso, os TIMPs possuem atividades biológicas independentes da sua ação inibitória sobre as MMPs, tais como: crescimento e diferenciação celular, migração celular, anti-angiogenese, e efeito anti-e pró-apoptótico, sendo que os receptores para tais ações ainda estão sendo investigados (Kandasamy, Chow et al 2009;Vanhoutte and Heymans 2010).…”