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Am J Physiol Heart Circ Physiol 296: H887-H892, 2009. First published January 30, 2009; doi:10.1152/ajpheart.00750.2008
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Restoration of contractility in hyperhomocysteinemia by cardiac-specific deletion of NMDA-R1

Karni S. Moshal, Munish Kumar, Neetu Tyagi, Paras K. Mishra, Naira Metreveli, Walter E. Rodriguez, and Suresh C. Tyagi

Department of Physiology and Biophysics, School of Medicine University of Louisville, Louisville, Kentucky

Submitted 18 July 2008 ; accepted in final form 26 January 2009

Homocysteine (HCY) activated mitochondrial matrix metalloproteinase-9 and led to cardiomyocyte dysfunction, in part, by inducing mitochondrial permeability (MPT). Treatment with MK-801 [N-methyl-D-aspartate (NMDA) receptor antagonist] ameliorated the HCY-induced decrease in myocyte contractility. However, the role of cardiomyocyte NMDA-receptor 1 (R1) activation in hyperhomocysteinemia (HHCY) leading to myocyte dysfunction was not well understood. We tested the hypothesis that the cardiac-specific deletion of NMDA-R1 mitigated the HCY-induced decrease in myocyte contraction, in part, by decreasing nitric oxide (NO). Cardiomyocyte-specific knockout of NMDA-R1 was generated using cre/lox technology. NMDA-R1 expression was detected by Western blot and confocal microscopy. MPT was determined using a spectrophotometer. Myocyte contractility and calcium transients were studied using the IonOptix video-edge detection system and fura 2-AM loading. We observed that HHCY induced NO production by agonizing NMDA-R1. HHCY induced the MPT by agonizing NMDA-R1. HHCY caused a decrease in myocyte contractile performance, maximal rate of contraction and relaxation, and prolonged the time to 90% peak shortening and 90% relaxation by agonizing NMDA-R1. HHCY decreased contraction amplitude with the increase in calcium concentration. The recovery of calcium transient was prolonged in HHCY mouse myocyte by agonizing NMDA-R1. It was suggested that HHCY increased mitochondrial NO levels and induced MPT, leading to the decline in myocyte mechanical function by agonizing NMDA-R1.

mitochondrial matrix metalloproteinase; myocyte mechanics; calcium transient; mitochondrial permeability; N-methyl-D-aspartate receptor 1


Address for reprint requests and other correspondence: S. C. Tyagi, Dept. of Physiology and Biophysics, 500 S. Preston St., HSC Bldg. A-1115, Univ. of Louisville, Louisville, KY 40202 (e-mail: s0tyag01{at}louisville.edu)






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