Intracellular Action of Matrix Metalloproteinase-2 Accounts for Acute Myocardial Ischemia and Reperfusion Injury

Abstract

Background-Matrix metalloproteinases are best recognized for their ability to degrade the extracellular matrix in both physiological and pathological conditions. However, recent findings indicate that some of them are also involved in mediating acute processes such as platelet aggregation and vascular tone. The acute contractile defect of the heart after ischemia-reperfusion may involve the proteolytic degradation of the thin filament protein troponin I; however, the protease responsible for this remains obscure. Methods and Results-Here we report that matrix metalloproteinase-2 is colocalized with troponin I within the thin myofilaments of cardiomyocytes in ischemic-reperfused hearts and that troponin I is a novel intracellular target for proteolytic cleavage by matrix metalloproteinase-2. Inhibition of matrix metalloproteinase-2 activity prevented ischemia-reperfusion-induced troponin I degradation and improved the recovery of mechanical function of the heart. Conclusions-These data reveal for the first time a novel molecular mechanism by which matrix metalloproteinase-2 causes acute myocardial dysfunction after ischemia-reperfusion injury and that matrix metalloproteinase-2 has a biological action within the cell.

Heart Failure, Myocardial Stunning, and Troponin: A Key Regulator of the Cardiac Myofilament

“…40,41 One group dissociated TnI proteolysis from stunning and found that stretch of the heart contributes to TnI proteolysis in global ischemia/reperfusion; 42 however, others found that TnI proteolysis correlated with functional changes and measures that reduced proteolysis of TnI ameliorated stunning. [43][44][45] There is also controversy as to whether TnI proteolysis occurs in the human heart. There is evidence for and against TnI proteolysis in the setting of cardiac ischemic disease.…”

“…45,49 Proteolysis of other myofilament proteins have also been associated with ischemia reperfusion in low-flow regional models in dogs, including TnT and MyBP-C. 40,50 Caspase-mediated partial proteolysis may also play a role in myofilament protein injury in HF. 51 The controversies in this area, as well as the lack of definitive data to correlate modifications of myofilament proteins with contractile dysfunction, suggest that additional experimental work is necessary.…”

Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses

“…However, recent studies are clearly showing that MMP-2 may have many other targets unrelated to the extracellular matrix, including intracellular substrates [11,12] and other mediators possibly affecting the vascular tone such as bigendothelin-1[13], calcitonin gene-related peptide [14] and adrenomedullin [15]. Importantly, activated MMP-2 has been shown to impair cardiac function possibly as a result of its activity targeting sarcomeric and cytoskeletal proteins such as troponin I, myosin light chain-1, a-actinin and titin [16][17][18][19][20].Recent studies indicate that MMPs, including MMP-2, are involved in proteolytic cleavage of b 1 -and b 2 -adrenoreceptors [21]. Rodrigues et al [22] demonstrated that the labelling density of the extracellular domain of b 2 -adrenergic receptor in aortic endothelial cells from Wistar rats was reduced after treatment with plasma of spontaneously hypertensive rats with increased MMPs levels, thus indicating cleavage of b 2 -adrenergic receptors.…”

“…However, recent studies are clearly showing that MMP-2 may have many other targets unrelated to the extracellular matrix, including intracellular substrates [11,12] and other mediators possibly affecting the vascular tone such as bigendothelin-1 [13], calcitonin gene-related peptide [14] and adrenomedullin [15]. Importantly, activated MMP-2 has been shown to impair cardiac function possibly as a result of its activity targeting sarcomeric and cytoskeletal proteins such as troponin I, myosin light chain-1, a-actinin and titin [16][17][18][19][20].…”

Trials, tribulations and speculation! Report from the 7th Biennial Hatter Cardiovascular Institute Workshop

“…However, more recently, MMPs have been demonstrated to have intracellular targets -cytoskeletal [2,3], contractile [4,5] and potentially also in terms of cell survival and cell death pathways [6,7]. Robert Bell and Derek Yellon presented data demonstrating that not only does MMP inhibition at reperfusion attenuate infarction in both in-vitro and in-vivo preparations, but the protection observed is additional to that seen following targeted deletion of the cyclophillin-D component of the mPTP.…”