Document Detail


Effect of hypercholesterolemia on myocardial necrosis and apoptosis in the setting of ischemia-reperfusion.
MedLine Citation:
PMID:  19752371     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
METHODS AND 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:
Robert M Osipov; Cesario Bianchi; Jun Feng; Richard T Clements; Yuhong Liu; Michael P Robich; Hilary P Glazer; Neel R Sodha; Frank W Sellke
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  120     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-15     Completed Date:  2009-10-06     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  S22-30     Citation Subset:  AIM; IM    
Affiliation:
Alpert School of Medicine at Brown University, Rhode Island Hospital, Providence, 02905, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Coronary Vessels / physiopathology
Hemodynamics
Hypercholesterolemia / pathology*,  physiopathology
Lipids / blood
Male
Myocardial Infarction / pathology
Myocardial Reperfusion Injury / pathology*,  physiopathology
Myocardium / pathology*
Necrosis
Nitric Oxide Synthase Type III / metabolism
Oxidative Stress
Peroxidase / metabolism
Swine
Ventricular Fibrillation / etiology
p38 Mitogen-Activated Protein Kinases / metabolism
Grant Support
ID/Acronym/Agency:
HL69024/HL/NHLBI NIH HHS; HL85647/HL/NHLBI NIH HHS; R01 HL046716-17/HL/NHLBI NIH HHS; R01 HL069024-07/HL/NHLBI NIH HHS; R01 HL085647-02/HL/NHLBI NIH HHS; R01 HL46716/HL/NHLBI NIH HHS; T32 HL076130-05/HL/NHLBI NIH HHS; T32-HL076130/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Lipids; EC 1.11.1.7/Peroxidase; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases
Comments/Corrections

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