Effects of hypercholesterolemia on myocardial ischemia-reperfusion injury in LDL receptor-deficient mice.
Hypercholesterolemia is a primary risk factor for atherosclerosis, coronary artery disease, and myocardial infarction. We subjected low density lipoprotein receptor-deficient (LDLr -/-) and control (wild-type) mice to 30 minutes of myocardial ischemia and 120 minutes of reperfusion. Myocardial infarction per area at risk (AAR) was noted under baseline conditions to be significantly (P<0.05) smaller in the LDLr -/- mice compared with wild-type mice (24.7+/-3. 2% and 38.8+/-4.3% of AAR, respectively). Subsequently, mice were fed a high-cholesterol diet (HCD) for 2 or 12 weeks, which resulted in significant increases in serum cholesterol levels in both LDLr -/- and wild-type groups. After 2 weeks of the HCD, the LDLr -/- mice demonstrated a significant elevation (P<0.01) in myocardial necrosis per AAR (50.2+/-5.36% of AAR) compared with the normal-diet LDLr -/- group, whereas the short-term HCD-fed wild-type mice demonstrated no significant difference from baseline. In contrast, wild-type mice fed the HCD for 12 weeks revealed a significant (P<0. 05) decrease in necrosis per AAR, which was 22.5+/-3.2% of the AAR in comparison with that in the normal-diet wild-type mice (38.8+/-4. 3% of AAR). LDLr -/- mice on the same long-term HCD showed a similar significantly (P<0.05) decreased infarct size, which was 13.2+/-4.0% of the AAR. In additional experiments, we determined that myocardial tissue total glutathione (GSH) levels were reduced after 2 weeks of the HCD and were significantly increased after 12 weeks of the HCD in the LDLr -/- mouse heart. These data suggest that short-term cholesterol feeding renders the myocardium of LDLr -/- mice more susceptible to ischemia-reperfusion injury, whereas more long-term hypercholesterolemia confers cardioprotection in the LDLr -/- mouse heart.
Girod
W G
WG
Department of Surgery, LSU Medical Center, Shreveport, LA 71130, USA.
Jones
S P
SP
Sieber
N
N
Aw
T Y
TY
Lefer
D J
DJ
D000818:Animals; D001794:Blood Pressure; D002784:Cholesterol / Q000097:blood; D005978:Glutathione / Q000032:analysis; D006937:Hypercholesterolemia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000737:chemistry; D009504:Neutrophils / Q000166:cytology; D011973:Receptors, LDL / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D005978:Glutathione