Abstract
BackgroundDiabetic cardiomyopathy (DM CMP) is defined as cardiomyocyte damage and ventricular dysfunction directly associated with diabetes independent of concomitant coronary artery disease or hypertension. Matrix metalloproteinases (MMPs), especially MMP-2, have been reported to underlie the pathogenesis of DM CMP by increasing extracellular collagen content.PurposeWe hypothesized that two discrete MMP-2 isoforms (full length MMP-2, FL-MMP-2; N-terminal truncated MMP-2, NTT-MMP-2) are induced by high glucose stimulation in vitro and in an experimental diabetic heart model.MethodsRat cardiomyoblasts (H9C2 cells) were examined to determine whether high glucose can induce the expression of the two isoforms of MMP-2. For the in vivo study, we used the streptozotocin-induced DM mouse heart model and age-matched controls. The changes of each MMP-2 isoform expression in the diabetic mice hearts were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical stains were conducted to identify the location and patterns of MMP-2 isoform expression. Echocardiography was performed to compare and analyze the changes in cardiac function induced by diabetes.ResultsQuantitative RT-PCR and immunofluorescence staining showed that the two MMP-2 isoforms were strongly induced by high glucose stimulation in H9C2 cells. Although no definite histologic features of diabetic cardiomyopathy were observed in diabetic mice hearts, left ventricular systolic dysfunction was determined by echocardiography. Quantitative RT-PCR and IHC staining showed this abnormal cardiac function was accompanied with the increases in the mRNA levels of the two isoforms of MMP-2 and related to intracellular localization.ConclusionTwo isoforms of MMP-2 were induced by high glucose stimulation in vitro and in a Type 1 DM mouse heart model. Further study is required to examine the role of these isoforms in DM CMP.
Highlights
Diabetic cardiomyopathy (DM-CMP) is defined as diabetes mellitus (DM)-induced ventricular dysfunction independent of concomitant coronary artery disease or hypertension [1,2]
Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence staining showed that the two Matrix metalloproteinases (MMPs)-2 isoforms were strongly induced by high glucose stimulation in H9C2 cells
No definite histologic features of diabetic cardiomyopathy were observed in diabetic mice hearts, left ventricular systolic dysfunction was determined by echocardiography
Summary
Diabetic cardiomyopathy (DM-CMP) is defined as diabetes mellitus (DM)-induced ventricular dysfunction independent of concomitant coronary artery disease or hypertension [1,2]. Previous reports have indicated that specific matrix metalloproteinases (MMPs) play important roles in several forms of cardiac disease, including ischemia-reperfusion (I/R) injury, post-infarction left ventricular remodeling, heart failure, and dilated cardiomyopathy [8,9,10,11]. Matrix metalloproteinase-2 (MMP-2) has been extensively studied in both experimental models and human cardiac disease and has been a therapeutic target in a limited number of clinical trials [12,13,14]. Until recently, both experimental and human studies were focused on the pathophysiologic roles of the full length MMP-2 isoform (FL-MMP-2), which has both extra- and intracellular proteolytic targets. We hypothesized that two discrete MMP-2 isoforms (full length MMP-2, FL-MMP-2; N-terminal truncated MMP-2, NTT-MMP-2) are induced by high glucose stimulation in vitro and in an experimental diabetic heart model
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