期刊论文详细信息
International Journal of Physiology, Pathophysiology and Pharmacology | |
Synergism between arrhythmia and hyperhomo-cysteinemia in structural heart disease | |
Neetu Tyagi1  Natia Qipshidze1  Paras K Mishra1  Srikanth Givvimani1  Utpal Sen1  Suresh C Tyagi1  | |
关键词: A-V fistula; MMP-9; connexin; NO; endothelial myocyte coupling; PVC; mitochondria; calpain; NOX4; peroxiredoxin; heart failure; | |
DOI : | |
学科分类:生理学与病理学 | |
来源: e-Century Publishing Corporation | |
【 摘 要 】
Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) is associated with cardiac arrhythmia and sudden cardiac death (SCD). Hcy increases iNOS, activates matrix metalloproteinase (MMP), disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) interupt cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling. We hypothesize that Hcy increases mtNOS, metalloproteinase activity, disrupts connexin-43, exacerbates endothelial-myocyte uncoupling, and induces cardiac failure by activating NMDA-R1 in structural heart disease. Chronic volume overload heart failure was created by aorta-venacava (AV) fistula. HHcy was induced by adminstrering Hcy in drinking water. NMDA-R1 was blocked by dizocilpine (MK-801). EKG and M-mode Echocardiography was performed. The E-M coupling was determined in cardiac rings. LV mitochondria was isolated. Levels of NMDA-R1, peroxiredoxin, NOX4, and mtNOS were measured. The degradation of connexin-43, collagen and elastin was measured by Western blot analysis. Mouse cardiac endothelial cells were cultured with or without Hcy or MK-801. The results suggest systolic and diastolic heart failure in HHcy and AVF mice. The levels of connexin, collagen degradation and MMP-9 were increased. The elastin was decreased in HHcy and AVF hearts. The mitochondrial NOX4 increased and peroxiredoxin was decreased. The mtNOS activity was synergistically increased in HHcy, AVF and HHcy+AVF hearts. The cardiac contraction and endothelial dependent relaxation was attenutated in HHcy and AVF hearts. Interestingly, the treatment with MK-801 mitigated the contractile dysfunction. These studies delineated the mechanism of Hcy-dependent endothelial-myocyte uncoupling in cardiac arrhythmia and failure, and have therapeutic ramifications for sudden cardiac death.【 授权许可】
Unknown
【 预 览 】
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