title: Cyclosporin A in left ventricular remodeling after myocardial infarction.
abstract: Recent studies suggest that an increase in apoptosis within the myocardium may be a contributing factor for the progression of late adverse left ventricular (LV) remodeling following myocardial infarction (MI). Given that apoptosis is often triggered by induction of the mitochondrial permeability transition (MPT) pore, the goal of this study was to evaluate the therapeutic efficacy of cyclosporin A (CsA), an MPT blocker, to prevent cells from undergoing apoptosis and consequently attenuate late LV remodeling post-MI. MI was induced in C57BL/6 mice and then randomized to either vehicle or CsA groups. Beginning 48 h after surgery after infarction had already occurred, mice were gavaged with CsA (2 mg/kg) or vehicle once daily. LV end-diastolic volume and LV ejection fraction were assessed by echocardiography before MI induction and terminally at either 7 days (n = 7) or 28 days (n = 8) post-MI. LV end-diastolic volume increased and LV ejection fraction decreased in all MI groups with no difference between the CsA-treated and untreated groups. After vehicle and CsA, areas of necrosis were present at 7 and 28 days post-MI with no difference between treatment groups. Caspase-3 activity and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling in distal nonnecrotic LV both increased after MI but were lower in CsA-treated mice compared with vehicle (P < 0.05). In conclusion, CsA decreased apoptosis occurring late after MI, confirming involvement of a CsA-sensitive MPT in the cell death. However, CsA-mediated reduction in apoptosis in non-MI myocardium was not beneficial against late pump dysfunction occurring during post-MI remodeling.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Andaleb
authors.initials: A
authors.lastname: Kholmukhamedov
authors.forename: Christina
authors.initials: C
authors.lastname: Logdon
authors.forename: Jiangting
authors.initials: J
authors.lastname: Hu
authors.forename: Richard A
authors.initials: RA
authors.lastname: McKinney
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004562:Electrocardiography; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013318:Stroke Volume / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D016572:Cyclosporine
keywords: TUNEL; apoptosis; caspase-3; mice mitochondrial permeabililty transition; necrosis; pump dysfunction