%0 Journal Article
%T N-n-Butyl Haloperidol Iodide Ameliorates Cardiomyocytes Hypoxia/Reoxygenation Injury by Extracellular Calcium-Dependent and -Independent Mechanisms
%A Yanmei Zhang
%A Gaoyong Chen
%A Shuping Zhong
%A Fuchun Zheng
%A Fenfei Gao
%A Yicun Chen
%A Zhanqin Huang
%A Wenfeng Cai
%A Weiqiu Li
%A Xingping Liu
%A Yanshan Zheng
%A Han Xu
%A Ganggang Shi
%J Oxidative Medicine and Cellular Longevity
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/912310
%X N-n-butyl haloperidol iodide (F2) has been shown to antagonize myocardial ischemia/reperfusion injury by blocking calcium channels. This study explores the biological functions of ERK pathway in cardiomyocytes hypoxia/reoxygenation injury and clarifies the mechanisms by which F2 ameliorates cardiomyocytes hypoxia/reoxygenation injury through the extracellular-calcium-dependent and -independent ERK1/2-related pathways. In extracellularcalcium-containing hypoxia/reoxygenation cardiomyocytes, PKC¦Á and ERK1/2 were activated, Egr-1 protein level and cTnI leakage increased, and cell viability decreased. The ERK1/2 inhibitors suppressed extracellular-calcium-containing-hypoxia/reoxygenation-induced Egr-1 overexpression and cardiomyocytes injury. PKC¦Á inhibitor downregulated extracellularcalcium-containing-hypoxia/reoxygenation-induced increase in p-ERK1/2 and Egr-1 expression. F2 downregulated hypoxia/reoxygenation-induced elevation of p-PKC¦Á, p-ERK1/2, and Egr-1 expression and inhibited cardiomyocytes damage. The ERK1/2 and PKC¦Á activators antagonized F2¡¯s effects. In extracellular-calcium-free-hypoxia/reoxygenation cardiomyocytes, ERK1/2 was activated, LDH and cTnI leakage increased, and cell viability decreased. F2 and ERK1/2 inhibitors antagonized extracellular-calcium-free-hypoxia/reoxygenation-induced ERK1/2 activation and suppressed cardiomyocytes damage. The ERK1/2 activator antagonized F2¡¯s above effects. F2 had no effect on cardiomyocyte cAMP content or PKA and Egr-1 expression. Altogether, ERK activation in extracellular-calcium-containing and extracellular-calcium-free hypoxia/reoxygenation leads to cardiomyocytes damage. F2 may ameliorate cardiomyocytes hypoxia/reoxygenation injury by regulating the extracellular-calcium-dependent PKC¦Á/ERK1/2/Egr-1 pathway and through the extracellular-calcium-independent ERK1/2 activation independently of the cAMP/PKA pathway or Egr-1 overexpression. 1. Introduction The phenomenon of exacerbated tissue and organ damage produced by the restoration of blood flow after ischemia is known as ischemia/reperfusion (I/R) injury. Studies have demonstrated that this phenomenon takes place in a variety of tissues and organs such as the brain, heart, liver, lungs, kidneys, gastrointestinal tract, limbs, and skin. Myocardial I/R injury is a pathophysiological phenomenon commonly seen after ischemic heart disease and heart surgery. Reducing and eliminating this damage has become a hot topic in the field. N-n-Butyl haloperidol iodide (F2) is a new compound synthesized by our group. A series of previous studies have shown that
%U http://www.hindawi.com/journals/omcl/2013/912310/