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, Suresh C. Tyagi

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)H887-H892
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume296
Issue number3
DOIs
StatePublished - Mar 1 2009

Fingerprint

Hyperhomocysteinemia
N-Methyl-D-Aspartate Receptors
Muscle Cells
Permeability
Homocysteine
Cardiac Myocytes
Nitric Oxide
Calcium
Dizocilpine Maleate
Fura-2
Matrix Metalloproteinase 9
Confocal Microscopy
Western Blotting
Technology

Keywords

  • Calcium transient
  • Mitochondrial matrix metalloproteinase
  • Mitochondrial permeability
  • Myocyte mechanics
  • N-methyl-d-aspartate receptor 1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Restoration of contractility in hyperhomocysteinemia by cardiac-specific deletion of NMDA-R1. / Moshal, Karni S.; Kumar, Munish; Tyagi, Neetu; Mishra, Paras K.; Metreveli, Naira; Rodriguez, Walter E.; Tyagi, Suresh C.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 296, No. 3, 01.03.2009, p. H887-H892.

Research output: Contribution to journalArticle

Moshal, Karni S. ; Kumar, Munish ; Tyagi, Neetu ; Mishra, Paras K. ; Metreveli, Naira ; Rodriguez, Walter E. ; Tyagi, Suresh C. / Restoration of contractility in hyperhomocysteinemia by cardiac-specific deletion of NMDA-R1. In: American Journal of Physiology - Heart and Circulatory Physiology. 2009 ; Vol. 296, No. 3. pp. H887-H892.
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