N-n-butyl haloperidol iodide ameliorates cardiomyocytes hypoxia/reoxygenation injury by extracellular calcium-dependent and -independent mechanisms.

Abstract

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, PKCα 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. PKCα inhibitor downregulated extracellularcalcium-containing-hypoxia/reoxygenation-induced increase in p-ERK1/2 and Egr-1 expression. F2 downregulated hypoxia/reoxygenation-induced elevation of p-PKCα, p-ERK1/2, and Egr-1 expression and inhibited cardiomyocytes damage. The ERK1/2 and PKCα 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 PKCα/ERK1/2/Egr-1 pathway and through the extracellular-calcium-independent ERK1/2 activation independently of the cAMP/PKA pathway or Egr-1 overexpression.

• Authors: Yanmei Zhang, Gaoyong Chen, Shuping Zhong, Fuchun Zheng, Fenfei Gao, Yicun Chen, Zhanqin Huang, Wenfeng Cai, Weiqiu Li, Xingping Liu, Yanshan Zheng, Han Xu, Ganggang Shi
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2013 Pg. 912310 ( 2013) ISSN: 1942-0994 [Electronic] United States
• PMID: 24392181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Early Growth Response Protein 1
• N-n-butyl haloperidol iodide
• Protein Kinase Inhibitors
• Troponin I
• Verapamil
• Cyclic AMP
• L-Lactate Dehydrogenase
• Extracellular Signal-Regulated MAP Kinases
• Haloperidol
• Oxygen
• Calcium

Topics

• Animals
• Calcium (pharmacology)
• Cell Hypoxia (drug effects)
• Cell Survival (drug effects)
• Cyclic AMP (metabolism)
• Cytoprotection (drug effects)
• Early Growth Response Protein 1 (metabolism)
• Enzyme Activation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Extracellular Space (drug effects, metabolism)
• Haloperidol (analogs & derivatives, pharmacology)
• L-Lactate Dehydrogenase (metabolism)
• Myocardium (pathology)
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Oxygen (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Troponin I (metabolism)
• Verapamil (pharmacology)