Myocardial matrix metalloproteinase-2: inside out and upside down

Abstract

Since their inaugural discovery in the early 1960s, matrix metalloproteinases (MMPs) have been shown to mediate multiple physiological and pathological processes. In addition to their canonical function in extracellular matrix (ECM) remodeling, research in the last decade has highlighted new MMP functions, including proteolysis of novel substrates beyond ECM proteins, MMP localization to subcellular organelles, and proteolysis of susceptible intracellular proteins in those subcellular compartments. This review will provide a comparison of the extracellular and intracellular roles of MMPs, illustrating that MMPs are far more interesting than the one-dimensional view originally taken. We focus on the roles of MMP-2 in cardiac injury and repair, as this is one of the most studied MMPs in the cardiovascular field. We will highlight how understanding all dimensions, such as localization of activity and timing of interventions, will increase the translational potential of research findings. Building upon old ideas and turning them inside out and upside down will help us to better understand how to move the MMP field forward.

Keywords: Cardiovascular disease; Doxycycline; Heart failure; MMP-2; Myocardial ischemia and infarction; TIPTOP.

Fig. 1

MMP-2 targets to the cytosol of the myocyte, where it undergoes post-translational modifications. The 72 kDa form of MMP-2 can be activated extracellularly by proteases (e.g., plasminogen or MMP-14) to yield a 64 kDa active form. The 72 kDa form of MMP-2 can also be activated intracellularly by S-glutathiolation, in the presence of peroxynitrite induced by ischemia/reperfusion or pro-inflammatory cytokines. This activation occurs in the presence of glutathione and does not require proteolytic removal of the pro-domain. This active 72 kDa MMP-2 form targets susceptible intracellular proteins within the cardiomyocyte to induce contractile dysfunction. MMP-2 targets to the cytosol by at least two mechanisms: 1) An MMP-2 splice variant in cardiomyocytes lacks the secretory signal sequence, resulting in its intracellular retention. 2) The canonical MMP-2 signal sequence is inefficient, yielding MMP-2 that targets to both the endoplasmic reticulum for secretion as well as MMP-2 that targets to the cytosol. In addition, MMP-2 has been shown to be phosphorylated at several sites, which modulates its activity. GSH, glutathione; ONOO⁻, peroxynitrite; PKC, protein kinase C.

Fig. 2

MMP-2 intracellular substrates in the cardiac sarcomere. MMP-2 co-localizes with and proteolytically processes multiple sarcomeric proteins during ischemia/reperfusion. Included in the list of MMP-2 targets are troponin I (a thin myofilament component), myosin light chain-1 (a thick myofilament component), titin, α-actinin (a cytoskeletal protein found in the Z-disc). Titin is the largest mammalian protein, with one molecule spanning half the length of the sarcomere, from Z-disc to the M-line. C, titin C-terminus; N, titin N-terminus.