Arash Khorrami
1,2 
, Mojtaba Ziaee
1,3* , Maryam Rameshrad
4,2, Ailar Nakhlband
5,2 , Nasrin Maleki-Dizaji
2 , Alireza Garjani
2* 1 Medicinal Plants Research Center, Maragheh University of Medical Sciences, Maragheh, Iran
2 Department of Pharmacology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
3 Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
4 Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
5 Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
Abstract
Introduction: 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.
Methods: 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.
Results: 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.
Conclusion: 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.