Targeting MMP-2 to treat ischemic heart injury

Abstract

Matrix metalloproteinase (MMPs) are long understood to be involved in remodeling of the extracellular matrix. However, over the past decade, it has become clear that one of the most ubiquitous MMPs, MMP-2, has numerous intracellular targets in cardiac myocytes. Notably, MMP-2 proteolyzes components of the sarcomere, and its intracellular activity contributes to ischemia-reperfusion injury of the heart. Together with the well documented role played by MMPs in the myocardial remodeling that occurs following myocardial infarction, this has led to great interest in targeting MMPs to treat cardiac ischemic injury. In this review we will describe the expanding understanding of intracellular MMP-2 biology, and how this knowledge may lead to improved treatments for ischemic heart injury. We also critically review the numerous preclinical studies investigating the effects of MMP inhibition in animal models of myocardial infarction and ischemia-reperfusion injury, as well as the recent clinical trials that are part of the effort to translate these results into clinical practice. Acknowledging the disappointing results of past clinical trials of MMP inhibitors for other diseases, we discuss the need for carefully designed preclinical and clinical studies to avoid mistakes that have been previously made. We conclude that inhibition of MMPs, and in particular MMP-2, shows promise as a therapy to prevent the progression from ischemic injury to heart failure. However, it is critical that the full breadth of MMP-2 biology be taken into account as such therapies are developed.

Matrix metalloproteinases and their tissue inhibitor after reperfused ST-elevation myocardial infarction treated with doxycycline. Insights from the TIPTOP trial

“…However, higher concentrations of TIMP-2 neutralize MMP-14 activity and prevent the activation of pro-MMP-2 [45]. This loss of MMP-2 activity as a function of TIMP-2 supports our results, particularly if we consider the unique role [46] played by the activation of MMP-2 on ischemia/reperfusion injury through the rapid proteolysis of sarcomeric proteins [10][11][12]. Thus, it is possible to hypothesize that the favorable effect of doxycycline that we observed in the TIPTOP trial [24,33] may be due to the upregulation of TIMP-2 which, in turn, could lead to a favorable modulation of MMP activity during the early stage of a reperfused AMI at both extracellular and intracellular levels.…”

MCP-1-induced protein attenuates post-infarct cardiac remodeling and dysfunction through mitigating NF-κB activation and suppressing inflammation-associated microRNA expression

“…A strong up-regulation of TNF-a in Basic Res Cardiol (2015) 110: 26 Page 11 of 15 26 microinfarction after microembolization is associated with ventricular dysfunction [9]. MMP-9 is highly induced in response to inflammatory cytokines, and enhanced expression of MMP-9 has been linked to post-MI remodeling [4,10,21], and MMP-9 gene deletion or treatment with an MMP-9 active site inhibitor has been shown to modulate the cellular inflammatory response and improve post-MI remodeling [10,21]. Thus, cardiomyocyte-specific expression of MCPIP may modulate the cardiomyocyte function via timely resolving the post-infarct inflammatory process, leading to improve survival and post-MI cardiac remodeling.…”

Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure

“…Here we examined doxycycline (DOX), a tetracycline antibiotic which is a well-known antimicrobial [16] agent with minimal side-effects, even after long-term administration [17–19], as a possible new therapeutic agent for heart failure. DOX has a well established inhibitory effect on matrix metalloproteinases (MMP-2 and 9) [20, 21], which is believed to be the basis of its major protective effect in the acute phase of myocardial infarction and in the early phase of myocardial remodeling [22–24]. The aim of the present study was to further examine the protective effect of DOX in a postinfarction heart failure model and on a rat cardiomyocyte cell line.…”