Atorvastatin Preserves Cardiac Contractility via Reducing Matrix Metalloproteinase-2 Isoforms Expression in a Diabetic Heart Model

Abstract

Purpose We investigated whether atorvastatin can alleviate diabetic cardiomyopathy (DM CMP) by reducing intracellular matrix metalloproteinase-2 (MMP-2) isoform expression. Methods Rat cardiomyoblasts (H9C2 cells) were tested to determine whether atorvastatin treatment after high glucose could reduce the expression of the two isoforms of MMP-2. For the in vivo study, we used the streptozotocin murine model of Type I DM and age-matched controls. The changes of each MMP-2 isoform in the diabetic mice hearts were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical stains were conducted to identify MMP-2 isoform expression. Echocardiography was performed to compare and analyze the changes in cardiac function induced by diabetes and atorvastatin. Results Quantitative RT-PCR and immunofluorescence staining showed that the two MMP-2 isoforms strongly induced by high glucose stimulation were attenuated by atorvastatin treatment in H9C2 cells. Although no definite histologic features of diabetic cardiomyopathy were observed in diabetic mice, left ventricular systolic dysfunction observed in diabetic heart was also normalized by atorvastatin treatment by echocardiographic evaluation. These findings accompanied reduced TUNEL staining and mitochondrial morphological change in atorvastatin treated diabetic group. 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 attenuated with atorvastatin treatment Conclusion Atorvastatin attenuated deterioration of cardiac dysfunction induced by diabetic condition by reducing expression of two isoforms of MMP-2 in vitro and in a Type I diabetes heart model. The roles played by these isoforms and atorvastatin treatment in diabetic cardiomyopathy require further study.