Oxidized cholesterol exacerbates toll-like receptor 4 expression and activity in the hearts of rats with myocardial infarction

The present study examined the effects of high cholesterol and high oxidized-cholesterol diets on the myocardial expression of TLR4 and pro-inflammatory cytokine in rats.

Male Wistar rats were allocated into 6 groups and fed with a normal diet, cholesterol, and oxidized-cholesterol rich diets with or without isoproterenol-induced myocardial infarction. TLR4 and MyD 88 expression and levels tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were measured in the heart and serum.

Oxidized cholesterol-fed animals had higher serum levels of oxidized low-density lipoprotein (LDL) (263±13 ng/dL) than the cholesterol-fed animals (98±8 ng/dL; P<0.001). A high level of oxidized-LDL caused fibrotic cell formation and enhanced neutrophil infiltration in the absence of MI. Both cholesterol and oxidized-cholesterol upregulated TLR4 mRNA expression and increased TNF-α and IL-6 production in the hearts of rats with MI. In rats fed with oxidized-cholesterol the serum and myocardial levels of TNF-α (653±42 pg/mL, 1375±121 pg/100 mg, respectively) were higher than MI group (358±24 pg/mL, P<0.001 and 885±56 pg/100 mg, P<0.01). A significant correlation was seen between TLR4 expression and infarct size.

These findings suggest that cardiac TLR4 is preferentially upregulated by oxidized cholesterol in rats. Oxidized cholesterol may have a critical role in cardiac toxicity in the absence of pathological conditions.