The protective effects of N-n-butyl haloperidol iodide on myocardial ischemia-reperfusion injury in rats by inhibiting Egr-1 overexpression

摘要

Aims: Our previous studies have shown that N- n- butyl haloperidol iodide ( F (2)) can antagonize myocardial ischemia/ reperfusion ( I/ R) injury by blocking intracellular Ca2+ overload. The present study is to test the hypothesis that the protective effects of F-2 on myocardial I/ R injury is mediated by downregulating Egr- expression. Methods: The Sprague - Dawley rat myocardial I/ R model and cardiomyocyte hypoxia/ reoxygenation ( H/ R) model were established. With antisense Egr- 1 oligodeoxyribonucleotide ( ODN), the relationship between Egr- 1 expression and myocardial I/ R injury was investigated. Hemodynamic parameters, myeloperoxidase ( MPO), cardiac troponin I ( cTnl) and tumor necrosis factor-alpha ( TNF-alpha) were measured to assess the degree of injury and inflammation of myocardial tissues and cells. Egr- 1 mRNA and protein expressions were examined by Northern- blot and Western- blot analyses. Results: Treatment with antisense Egr- 1 ODN significantly reduced Egr- 1 protein expression and attenuated injury of myocardial tissues and cells. Meanwhile, treatment with F-2 significantly inhibited the overexpression of Egr- 1 mRNA and protein in myocardial tissues and cells. Consistent with downregulation of Egr- 1 expression by F (2), inflammation and other damages were significantly relieved evidenced by the amelioration of hemodynamics, the reduction in myocardial MPO activity as well as the decrease in leakage of cTnI and release of TNF-alpha from cardiomyocyte. Conclusions: These results suggested that the overexpression of Egr- 1 was causative in myocardial I/ R or H/ R injury, and F (2) could protect myocardial tissues and cells from I/ R or H/ R injury, which was largely due to the inhibition of Egr- 1 overexpresssion.