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. 1. MMPs General Characteristics Matrix metalloproteinases (MMPs) are proteolytic enzymes, which play significant roles in a range of physiological processes including morphogenesis, cartilage and bone repair, wound healing, cell migration, and angiogenesis. They are best known for their role in degradation of extracellular proteins and remodeling of the extracellular matrix. MMPs belong to a family of more than 25 enzymes that are not only structurally related but are also similar in substrate specificity [1–4]. Of these, the best known enzyme is matrix metalloproteinase-2 (MMP-2 or gelatinase A) and matrix metalloproteinase-9 (MMP-9 or gelatinase B). MMP-2, a constitutive enzyme, is found in almost all cell types and it degrades denatured collagen (gelatin) and collagen type IV (a component of the basement membrane) as well as other extracellular matrix proteins [5–7]. MMP-9 is a cytokine inducible MMP which is most commonly located in leukocytes [8–10]. Enzymes of this family possess a signal peptide, amino-terminal propeptide, a catalytic Zn binding site, and carboxy terminus domains [11–13]. Enhanced activity of MMPs, such as MMP-2 and MMP-9, is implicated in a variety of cardiovascular
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