Cholesterol feeding exacerbates myocardial injury in Zucker diabetic fatty rats

Abstract

We measured infarct size after coronary occlusion (30 min) and reperfusion (24 h) in genetic non-insulin-dependent Zucker diabetic fatty (ZDF) rats with and without 4-wk cholesterol feeding. Infarct size was similar in ZDF rats and lean control rats but was significantly larger in cholesterol-fed diabetic rats than in cholesterol-fed lean rats (P < 0.05). Plasma levels of glucose, insulin, and triglycerides were significantly higher in diabetic rats and were not influenced by cholesterol feeding. The increase in total plasma cholesterol induced by cholesterol feeding was significantly greater in diabetic rats than in lean rats (P < 0.05). A significant positive correlation was found between total plasma cholesterol and infarct size (P < 0.05). Myeloperoxidase activity, as an index of neutrophil accumulation, was significantly higher and expression of P-selectin was more marked in the ischemic myocardium of cholesterol-fed diabetic rats than of cholesterol-fed lean rats. Acetylcholine-induced endothelium-dependent relaxation (EDR) of aortic rings was markedly impaired in cholesterol-fed diabetic rats. Thus cholesterol feeding significantly exacerbated myocardial injury produced by coronary occlusion-reperfusion in non-insulin-dependent diabetic rats, possibly because of enhanced expression of P-selectin and impairment of EDR in the coronary bed.

Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning

“…Hearts of apolipoprotein E and low-density lipoprotein receptor double knockout mice (ApoE/LDLr Ϫ/Ϫ ) fed an atherogenic diet for 6 to 8 months had worse postischemic function and increased infarct size and troponin T release compared with genetic controls ). In genetic noninsulin-dependent Zucker diabetic fatty rats, 4-week cholesterol feeding increased infarct size (Hoshida et al, 2000). Increased susceptibility of the heart to acute ischemia has been also confirmed in hyperlipidemic patients during coronary angioplasty (Ungi et al, 2005).…”

Diabetic Cardiomyopathy Revisited

“…Although some controversy exists on whether diabetic hearts are more susceptible to injury when analyzed ex vivo, 31,56,60,71,72 most in vivo studies have supported a greater degree of reduction in LV function and accelerated LV remodeling in the hearts of diabetic animals after coronary artery ligation. 40,42,44,54,73,74 Thus, it is likely that the diabetic milieu and associated changes in the myocardium sensitize the diabetic heart to dysfunction after ischemic injury. Studies in models of type 2 diabetes mellitus and insulin resistance suggest that insulin resistance per se might contribute to reduced myocardial recovery after ischemia.…”

“…For example genetic models of obesity and insulin resistance such as Zucker rats and db/db mice and mice with diet-induced obesity and insulin resistance exhibit impaired recovery of cardiac function after in vivo coronary artery ligation. 40,42,73 Changes may be independent of infarct size, which is unchanged in models fed high-fat diets 74 but increased in db/db mice. 44 Moreover, treatment of Zucker rats with insulin sensitizing agents such as thiazolidinedione improves postischemic recovery in vitro and in vivo.…”

Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment

“…These changes increase myocardial oxygen utilization and can reduce the compensatory capacity of postinfarcted diabetic myocardium [168]. Although some controversy exists on whether diabetic hearts are more susceptible to injury when analyzed ex vivo [1,127,150,216], most in vivo studies have supported a greater degree of reduction in LV function and accelerated LV remodeling in the hearts of diabetic animals after coronary artery ligation [82,95,155,186,200]. Several studies in the models of type 2 DM and insulin resistance suggest that insulin resistance per se might contribute to reduced myocardial recovery after ischemia [82,95].…”