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Effects of hypercholesterolemia on myocardial ischemia-reperfusion injury in LDL receptor-deficient mice
W G Girod1, S P Jones, N Sieber
1Department of Surgery, LSU Medical Center, Shreveport, LA 71130, USA.
Insights
Short-term high cholesterol diets increase heart attack risk in LDL receptor-deficient mice, while long-term feeding offers protection. This study investigates hypercholesterolemia
Area of Science:
- Cardiovascular Science
- Metabolic Research
- Ischemia-Reperfusion Injury
Background:
- Hypercholesterolemia is a key risk factor for atherosclerosis and coronary artery disease.
- Low-density lipoprotein receptor-deficient (LDLr-/-) mice are a model for studying cholesterol metabolism.
- Myocardial ischemia-reperfusion injury is a critical concern in cardiovascular disease.
Purpose of the Study:
- To investigate the impact of short-term and long-term high-cholesterol diets on myocardial ischemia-reperfusion injury in LDLr-/- mice.
- To compare the effects of diet-induced hypercholesterolemia in LDLr-/- mice versus wild-type controls.
- To explore the relationship between cholesterol levels, glutathione (GSH) levels, and infarct size.
Main Methods:
- Utilized LDL receptor-deficient (LDLr-/-) and wild-type mice.
- Subjected mice to a controlled protocol of myocardial ischemia (30 minutes) followed by reperfusion (120 minutes).
- Administered a high-cholesterol diet (HCD) for 2 weeks (short-term) and 12 weeks (long-term), with normal diet controls.
Main Results:
- Baseline, LDLr-/- mice had smaller infarct sizes compared to wild-type mice.
- Short-term HCD (2 weeks) significantly increased myocardial necrosis in LDLr-/- mice, but not wild-type mice.
- Long-term HCD (12 weeks) significantly decreased infarct size in both LDLr-/- and wild-type mice, with greater reduction in LDLr-/- mice.
- Myocardial glutathione (GSH) levels decreased after short-term HCD and increased after long-term HCD in LDLr-/- mice.
Conclusions:
- Short-term hypercholesterolemia exacerbates ischemia-reperfusion injury in LDLr-/- mice.
- Long-term hypercholesterolemia confers a cardioprotective effect against ischemia-reperfusion injury in LDLr-/- mice.
- Diet-induced hypercholesterolemia influences myocardial susceptibility to injury, potentially mediated by changes in GSH levels.
Abstract:
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.
