Mitochondrial matrix metalloproteinase activation decreases myocyte contractility in hyperhomocysteinemia
- 1 August 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 295 (2), H890-H897
- https://doi.org/10.1152/ajpheart.00099.2008
Abstract
Cardiomyocyte N-methyl-d-aspartate receptor-1 (NMDA-R1) activation induces mitochondrial dysfunction. Matrix metalloproteinase protease (MMP) induction is a negative regulator of mitochondrial function. Elevated levels of homocysteine [hyperhomocysteinemia (HHCY)] activate latent MMPs and causes myocardial contractile abnormalities. HHCY is associated with mitochondrial dysfunction. We tested the hypothesis that HHCY activates myocyte mitochondrial MMP (mtMMP), induces mitochondrial permeability transition (MPT), and causes contractile dysfunction by agonizing NMDA-R1. The C57BL/6J mice were administered homocystinemia (1.8 g/l) in drinking water to induce HHCY. NMDA-R1 expression was detected by Western blot and confocal microscopy. Localization of MMP-9 in the mitochondria was determined using confocal microscopy. Ultrastructural analysis of the isolated myocyte was determined by electron microscopy. Mitochondrial permeability was measured by a decrease in light absorbance at 540 nm using the spectrophotometer. The effect of MK-801 (NMDA-R1 inhibitor), GM-6001 (MMP inhibitor), and cyclosporine A (MPT inhibitor) on myocyte contractility and calcium transients was evaluated using the IonOptix video edge track detection system and fura 2-AM. Our results demonstrate that HHCY activated the mtMMP-9 and caused MPT by agonizing NMDA-R1. A significant decrease in percent cell shortening, maximal rate of contraction (−dL/dt), and maximal rate of relaxation (+dL/dt) was observed in HHCY. The decay of calcium transient amplitude was faster in the wild type compared with HHCY. Furthermore, the HHCY-induced decrease in percent cell shortening, −dL/dt, and +dL/dt was attenuated in the mice treated with MK-801, GM-6001, and cyclosporin A. We conclude that HHCY activates mtMMP-9 and induces MPT, leading to myocyte mechanical dysfunction by agonizing NMDA-R1.This publication has 36 references indexed in Scilit:
- Transgenic MMP-2 expression induces latent cardiac mitochondrial dysfunctionBiochemical and Biophysical Research Communications, 2007
- Homocysteine, brain natriuretic peptide and chronic heart failure: a critical reviewcclm, 2007
- Na+“Fuzzy Space”: Does It Exist, and Is It Important In Ischemic Injury?Journal of Cardiovascular Electrophysiology, 2006
- Selective Induction of Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Atrial and Ventricular Myocardium in Patients With Atrial FibrillationThe American Journal of Cardiology, 2006
- Relationship of Plasma Homocysteine with the Severity of Chronic Heart FailureClinical Chemistry, 2005
- Atrial Extracellular Matrix Remodeling and the Maintenance of Atrial FibrillationCirculation, 2004
- Alteration of NMDA NR 1 Receptors Within the Paraventricular Nucleus of Hypothalamus in Rats With Heart FailureCirculation Research, 2003
- Generation of Nitrotyrosine Precedes Activation of Metalloproteinase in Myocardium of Hyperhomocysteinemic RatsAntioxidants and Redox Signaling, 2002
- NMDA and Not Non-NMDA Receptor Antagonists Are Protective against Seizures Induced by Homocysteine in Neonatal RatsExperimental Neurology, 1994
- A convenient method forin situ processing of cultured cells for cytochemical localization by electron microscopyThe Journal of Pathology, 1985