Effects And Mechanisms Of Epidermal Growth Factor Receptor On Ischemia/Reperfusion Arrhythmias And Renal Hypertension

Effects and mechanisms of epidermal growth factor receptor on ischemia/reperfusion arrhythmias and renal hypertensionPart I Activation of epidermal growth factor receptor mediates myocardial ischemia/reperfusion arrhythmias in anaesthetized ratsAims:Epidermal growth factor receptor (EGFR) is a receptor protein tyrosine kinase and plays a critical role in the development and function of the heart. Previous studies have demonstrated that EGFR is involved in regulating electrical excitability of the heart. The present study was designed to investigate whether EGFR activation would mediate myocardial arrhythmias induced by ischemia/reperfusion in anaesthetized rats.Methods:Myocardial ischemia/reperfusion arrhythmias were induced by 10 min ligation of the left anterior descending coronary artery, followed by a 30 min reperfusion in anaesthetized rats. The incidence of ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation et al.) during ischemia/reperfusion was monitored. Tyrosine phosphorylation levels of both myocardial EGFR and major cardiac ion channels were determined by immunoprecipitation and Western blot analysis. In addition, the incidence of ischemia/reperfusion-induced arrhythmias was estimated when EGFR was down-regulated by short interference RNA (siRNA).Results:Incidence and severity of cardiac arrhythmias were significantly reduced by pretreatment with the EGFR kinase inhibitor AG556. Phosphorylation level of myocardial EGFR was increased during ischemia and at early reperfusion. Intramyocardial transfection of EGFR siRNA reduced EGFR mRNA and protein, and decreased the incidence of ventricular fibrillation induced by reperfusion. Interestingly, tyrosine phosphorylation levels of cardiac Na+ channel (INa) and L-type Ca2+ channel (ICa.L) were significantly increased at corresponding time points to the alteration of phosphorylated EGFR level during reperfusion. AG556 pretreatment countered the increased tyrosine phosphorylation level of Na+ and L-type Ca2+ channels induced by reperfusion. No significant alteration was observed in tyrosine phosphorylation levels of cardiac Kv4.2 and Kir2.1 channels during the cardiac ischemia/reperfusion.Conclusion:These results demonstrate for the first time that EGFR plays an important role in the genesis of myocardial ischemia/reperfusion arrhythmias, which is likely mediated at least in part by enhancing tyrosine phosphorylation of cardiac Na+ and L-type Ca2+ channels.Partâ…¡Effects and mechanisms of epidermal growth factor receptor on cardiovascular remodeling in renal hypertensive ratsAims:Hypertension-induced cardiovascular remodeling is an independent risk factor resulting in acute cardiovascular accidents. Epidermal growth factor receptor (EGFR) is a receptor protein tyrosine kinase associated with many important cellular processes. A substantial body of evidence demonstrates that EGFR contributes to cardiac hypertrophy and vascular smooth muscle cell proliferation. Our current study was to determine the possibilities and mechanisms of EGFR responsible for cardiovascular remodeling in renal hypertensive rats.Methods:Classical two-kidney, one-clip (2K1C) Goldblatt hypertensive rats were used in the present study. Blood pressure was measured with the tail-cuff method. Left ventricular mass index (LVMI) and histopathological changes in the cardiovascular system were analysed. EGFR expressions of aortas and myocardium as well as phosphorylation levels of extracellular regulated proteinkinases (ERK) in hypertensive rats were detected by immunohistochemistry and Western blot analysis, respectively.Results:â‘ Systolic pressure was markedly increased 2 weeks after operation and reached a plateau after 3 weeks, which maintained more than 150 mmHg by the end of the experiment at the 6th week in 2K1C rats. These results suggested that Goldblatt hypertensive animal model was successfully established.â‘¡Left ventricular mass index (LVMI) was significantly elevated in rats subjected to 2K1C compared with sham group (P <0.05). Proliferation of collagen fibers in myocardial interstitium and around small blood vessels was confirmed by Masson staining in hypertensive rats.â‘¢Immunohistochemistry and Western blot analysis showed that EGFR expression in aortas and myocardium was increased associated with the up-regulated phosphorylation levels of ERK in blood pressure-dependent manner during Goldblatt hypertension.Conclusion:This study suggests that EGFR may be involved in cardiovascular remodeling in renal hypertensive rats. The underlying molecular mechanisms are in part likely to activate MAPK/ERK signal pathway. Our results provid the new insight into the prevention and treatment of cardiovascular remodeling induced by Goldblatt hypertension.