Intracellular Regulation of Matrix Metalloproteinase-2 Activity: New Strategies in Treatment and Protection of Heart Subjected to Oxidative Stress

Abstract

Much is known regarding cardiac energy metabolism in ischemia/reperfusion (I/R) injury. Under aerobic conditions, the heart prefers to metabolize fatty acids, which contribute to 60–80% of the required ATP. During ischemia, anaerobic glycolysis increases and becomes an important source of ATP for preservation of ion gradients. With reperfusion, fatty acid oxidation quickly recovers and again predominates as the major source of mitochondrial oxidative metabolism. Although a number of molecular mechanisms have been implicated in the development of I/R injury, their relative contributions remain to be determined. One such mechanism involves the proteolytic degradation of contractile proteins, such as troponin I (TnI), myosin heavy chain, titin, and the myosin light chains (MLC1 and MLC2) by matrix metalloproteinase-2 (MMP-2). However, very little is known about intracellular regulation of MMP-2 activity under physiological and pathological conditions. Greater understanding of the mechanisms that govern MMP-2 activity may lead to the development of new therapeutic strategies aimed at preservation of the contractile function of the heart subjected to myocardial infarction (MI) or I/R. This review discusses the intracellular mechanisms controlling MMP-2 activity and highlights a new intracellular therapeutic direction for the prevention and treatment of heart injury.

Tendon Extracellular Matrix Remodeling and Defective Cell Polarization in the Presence of Collagen VI Mutations

“…Although the active MMP2 protein was similarly increased in BM and UCMD conditioned media, the gelatinolytic activity was significantly increased only in the UCMD culture, pointing to a differential regulation of protein activity in UCMD with respect to BM. The regulation of MMP2 activity involves several mechanisms, such as transcription, regulation of mRNA half-life, secretion, intraor extracellular localization, enzyme activation, and inhibition by specific and nonspecific cellular protease inhibitors [34]; thus, determining the actors responsible for such a differential regulation in BM and UCMD requires further extensive studies.…”

The Role of Mitochondria and Oxidative/Antioxidative Imbalance in Pathobiology of Chronic Obstructive Pulmonary Disease

“…Metalloproteinases (MMPs) are proteolytic enzymes, which play roles in many physiological processes, including morphogenesis, cell migration, and angiogenesis [139]. Neutrophils secrete MMP-8, MMP-9, and serine proteases (neutrophil elastase, proteinase, and cathepsin G) [138].…”

Paralogues of Mmp11 and Timp4 Interact during the Development of the Myotendinous Junction in the Zebrafish Embryo

“…Furthermore, the furin recognition motif may also function as a nuclear localization signal in this context [80]. The intracellular roles of MMPs remain poorly understood, apart from increasing evidence that these proteases become activated under pathological conditions during which they participate in a variety of mechanisms resulting in cellular damage and death [45][46][47][48]77,81]. However, it seems unlikely that highly conserved mechanisms that concentrate these potentially dangerous proteases in structures like sarcomeres do not serve some physiologically advantageous processes of which we remain ignorant [49].…”