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

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.<br /> 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. <br /> 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.<br /> 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.

Signaling pathways and targeted therapy for myocardial infarction

“…In addition, some metabolism-related factors are also involved in the regulation of the TLR4/MyD88/NF-κB pathway as follows: HIF-1α and apolipoprotein A-I mimetic peptide 4F (4F) may attenuate myocardial injury by minimizing TLR4 upregulation in post-MI rats 228,229 ; cardiac TLR4 is preferentially upregulated by oxidized cholesterol in rats with MI 230 . Similarly, activation of the TLR4-MyD88 signaling pathway in a hyperlipidemic environment inhibits the lisinopril-mediated cardioprotective effect 231 .…”

The Impacts of Animal-Based Diets in Cardiovascular Disease Development: A Cellular and Physiological Overview

“…These detrimental effects may be due to TLR activation, as oxLDL particles mimic microbial pathogen-associated molecular patterns which can be recognized by TLRs [161], particularly TLR4 [62]. In Wistar rats, the consumption of oxidized cholesterol for 14 weeks resulted in a ~10% increase in left ventricle infarct size compared to control animals, while heart failure induction via isoproterenol was exacerbated by oxLDL (56% infarct size) compared with a standard diet without oxLDL (36% infarct size) [162]. These effects were tied to increased myocardial TLR4 mRNA, which mirrored changes in infarct sizes.…”

Cardiotoxicity induced by immune checkpoint inhibitor: The complete insight into mechanisms, monitoring, diagnosis, and treatment

“…A study by Blyszczuk et al ( 29 ) proved that the presence of the MyD-88 gene in patients enhanced the MyD-88/IL-1 axis function by promoting autoimmune-response of CD4+ cells. MyD-88 gene upregulates the genetic transcription of pro-inflammatory cytokines to flare inflammatory reactions and thus, plays a pivotal role in promoting fibrosis and progression toward myocarditis or heart failure ( 30 ). On the contrary, patients who were MyD-88 −/− had a diminished autoimmune response and thus were much less likely to develop myocarditis regardless of the triggers that patients were subjected to.…”