title: Calcineurin inhibition ameliorates structural, contractile, and electrophysiologic consequences of postinfarction remodeling.
abstract: BACKGROUND
  After myocardial infarction (MI), the heart undergoes an adaptive remodeling process characterized by hypertrophy of the noninfarcted myocardium. Calcineurin, a Ca2+-calmodulin-regulated phosphatase, has been shown to participate in hypertrophic signal transduction.
  
  
  RESULTS
  We investigated the effects of calcineurin inhibition by cyclosporin A on key structural, contractile, and electrophysiologic alterations of post-MI remodeling. Male Sprague-Dawley rats were divided into four groups: (1) sham-operated; (2) sham + cyclosporin A; (3) post-MI (left anterior descending coronary artery ligation); and (4) MI + cyclosporin A. Cyclosporin A (25 mg/kg/day) was initiated 2 days before surgery and continued for 30 days. Hypertrophy was evaluated by echocardiography and by changes in membrane capacitance of isolated myocytes from noninfarcted left ventricle (LV). The effects of cyclosporin A on hemodynamics and cardiac dimensions were investigated, and changes in diastolic function were correlated with changes in protein phosphatase 1 activity and the basal level of phosphorylated phospholamban. The effects of cyclosporin A on Kv4.2/Kv4.3 genes expression and transient outward K+ current (I(to)) density also were evaluated. One of 12 rats in the post-MI group and 2 of 12 rats in the post-MI + cyclosporin A group died within 48 hours after MI. There were no late deaths in either MI group. There was no evidence of heart failure (lung congestion and/or pleural effusion) in the two groups 4 weeks post-MI. Calcineurin phosphatase activity increased 1.9-fold in post-MI remodeled LV myocardium, and cyclosporin A administration resulted in an 86% decrease in activity. There were statistically significant decreases of LV end-diastolic pressure, LV end-diastolic diameter, and LV relative wall thickness in the post-MI + cyclosporin A group compared with the post-MI group. On the other hand, there was no significant difference in LV end-systolic diameter or peak rate of LV pressure increase between the two post-MI groups. Protein phosphatase 1 activity was elevated by 36% in the post-MI group compared with sham, and this correlated with a 79% decrease in basal level of p16-phospholamban. In the post-MI + cyclosporin A group, the increase in protein phosphatase 1 activity was much less (18% vs 36%; P < 0.05), and the decrease in basal level of p16-phospholamban was markedly ameliorated (20% vs 79%; P < 0.01). The decreases in mRNA levels of Kv4.2 and Kv4.3 and I(to) density in the LV of the post-MI + cyclosporin A group were significantly less compared with the post-MI group.
  
  
  CONCLUSIONS
  Our results show that calcineurin inhibition by cyclosporin A partially ameliorated post-MI remodeled hypertrophy, diastolic dysfunction, decrease in basal level of phosphorylated phospholamban, down-regulation of key K+ genes expression, and decrease of K+ current, with no adverse effects on systolic function or mortality in the first 4 weeks after MI.
authors.affiliation: Department of Medicine, State University of New York Health Science Center, Brooklyn 11203, USA.
authors.forename: L
authors.initials: L
authors.lastname: Deng
authors.forename: B
authors.initials: B
authors.lastname: Huang
authors.forename: D
authors.initials: D
authors.lastname: Qin
authors.forename: K
authors.initials: K
authors.lastname: Ganguly
authors.forename: N
authors.initials: N
authors.lastname: El-Sherif
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000503:physiopathology*; D054645:Protein Phosphatase 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D016572:Cyclosporine; D019703:Calcineurin; D054645:Protein Phosphatase 1