title: Effect of hypercholesterolemia on myocardial necrosis and apoptosis in the setting of ischemia-reperfusion.
abstract: BACKGROUND
  Hypercholesterolemia is prevalent in patients who experience myocardial ischemia-reperfusion injury (IR). We investigate the impact of dietary-induced hypercholesterolemia on the myocardium in the setting of acute IR.
  
  
  RESULTS
  In normocholesterolemic (NC, n=7) and hypercholesterolemic (HC, n=7) Yucatan male pigs, the left anterior descending coronary artery was occluded for 60 minutes, followed by reperfusion for 120 minutes. Hemodynamic values were recorded, and TTC staining was used to assess necrosis. Oxidative stress was measured. Specific cell death and survival signaling pathways were assessed by Western blot and TUNEL staining. Infarct size was 45% greater in HC versus NC (42% versus 61%, P<0.05), whereas the area at risk (AAR) was similar in both groups (P=0.61). Whereas global LV function (+dP/dt, P<0.05) was higher during entire period of IR in HC versus NC, regional function deteriorated more following reperfusion in HC (P<0.05). Ischemia increased indices of myocardial oxidative stress such as protein oxidation (P<0.05), lipid peroxidation (P<0.05), and nitrotyrosylation in HC versus NC, as well as the expression of phospho-eNOS (P<0.05). The expression of myeloperoxidase, p38 MAPK, and phospho-p38 MAPK was higher in HC versus NC (all P<05). Ischemia caused higher expression of the proapoptotic protein PARP (P<0.05), and lower expression of the prosurvival proteins Bcl2 (P<0.05), phospho-Akt, (P<0.05), and phospho-PKCepsilon (P<0.05) in the HC versus NC. TUNEL-positive cell count was 3.8-fold (P<0.05) higher in the AAR of HC versus NC.
  
  
  CONCLUSIONS
  This study demonstrates that experimental hypercholesterolemia is associated with increased myocardial oxidative stress and inflammation, attenuation of cell survival pathways, and induction of apoptosis in the ischemic territory, which together may account for the expansion of myocardial necrosis in the setting of acute IR.
authors.affiliation: Alpert School of Medicine at Brown University, Rhode Island Hospital, Providence, 02905, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Osipov
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Robich
authors.forename: Hilary P
authors.initials: HP
authors.lastname: Glazer
authors.forename: Neel R
authors.initials: NR
authors.lastname: Sodha
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000818:Animals; D017209:Apoptosis; D003331:Coronary Vessels / Q000503:physiopathology; D006439:Hemodynamics; D006937:Hypercholesterolemia / Q000473:pathology* / Q000503:physiopathology; D008055:Lipids / Q000097:blood; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology*; D009336:Necrosis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D013552:Swine; D014693:Ventricular Fibrillation / Q000209:etiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D008055:Lipids; D009195:Peroxidase; D052250:Nitric Oxide Synthase Type III; D048051:p38 Mitogen-Activated Protein Kinases