Mitochondrial MMP activation decreases myocyte contractility in hyperhomocysteinemia.

Abstract

Hyperhomocysteinemia (HHCY) is associated with mitochondrial dysfunction. Matrix metalloproteinase protease (MMP) activation causes mitochondrial dysfunction. We tested the hypothesis that HCY activates myocyte mitochondrial MMP (mtMMP), induces mitochondrial permeability transition (MPT), and causes contractile dysfunction. Mice were administered HCY (0.6g/L) in drinking water for 10 wks. The mtMMP activity was measured by zymography. MPT was measured by decrease in light absorbance at 540 nm. Cellular calcium transients were detected using IonOptix edge detection system. The effect of MK‐801(NMDA‐R1 blocker), GM6001 (MMP blocker), and cyclosporine A (MPT blocker) on myocyte contractility was evaluated. HHCY induced the mtMMP‐9 and caused MPT. Calcium decay was faster in WT compared to HHCY. A decrease in cell shortening, maximal rate of contraction (−dL/dt), and maximal rate of relaxation (+dL/dt) was observed in HHCY (Fig. 1). Furthermore, HHCY‐induced decrease in cell shortening, −dL/dt, +dL/dt was attenuated with MK‐801, GM6001, and cyclosporine A. We conclude that HHCY activates mtMMP‐9, increases MPT leading to decrease in contractility by activating NMDA‐R1. This study was supported by AHA post‐doctoral training to KSM and NIH to SCT.