L-carnitine ameliorates myocardial injury by alleviating endoplasmic reticulum stress via inhibition of PERK pathway in exertional heatstroke rats

Abstract

Exertional heatstroke (EHS) is a life-threatening condition with potential for tissues and organs injury, including heart. Effective drug strategies to treat patients with EHS are warranted to unlock the therapeutic potential. Considering the cardioprotective effects of L-carnitine (LC), this study aimed to investigate the effects of LC on EHS-induced myocardial injury in rats and to explore the underlying mechanisms. Here, we found that LC exerted a greater protective effect on EHS-induced cardiac dysfunction and mortality, which also significantly attenuated certain negative effects, including increased myocardial apoptosis, pathological changes, and ultrastructural impairment, enhanced activity levels of such serum enzymes as AST, LDH, CK, and CK-MB, reduced BCL-2 expression, increased the expression of cleaved caspase-3 and the critical endoplasmic reticulum stress (ERS) indices like CHOP and GRP78 in EHS rats. Besides, pretreatment of EHS rats with PBA (4-Phenyl butyric acid), a chemical chaperone that attenuates ERS, restored BCL-2 expression, reduced the protein levels of cleaved caspase-3, CHOP, and GRP78. Furthermore, thapsigargin (TG), which induces ERS, enhanced the expression of BAX, cleaved caspase-3, CHOP, and GRP78, attenuated BCL-2 expression, and enhanced mitochondrial impairment in EHS + LC rats. Mechanismly, the protective effects of LC were mediated, at least partly, by inhibiting the activation of PERK pathway against ERS-associated myocardial damage. These results indicate that supplementation of LC might be a potential strategy to reduce myocardial injury by affecting ERS via inhibiting the PERK pathway against EHS.

Keywords

• L-carnitine
• Exertional heatstroke
• Myocardial apoptosis
• Endoplasmic reticulum stress
• Mitochondrial damage