Abstract
Heat stroke (HS) is a life-threatening illness and defined as when body temperature elevates above 40°C accompanied by the systemic inflammatory response syndrome that results in multiple organ dysfunctions. α-Lipoic acid (ALA) acts as a cofactor of mitochondrial enzymes and exerts anti-inflammatory and antioxidant properties in a variety of diseases. This study investigates the beneficial effects of ALA on myocardial injury and organ damage caused by experimental HS and further explores its underlying mechanism. Male Wistar rats were exposed to 42°C until their rectal core temperature reached 42.9°C and ALA was pretreared 40 or 80 mg/kg (i.v.) 1.5 h prior to heat exposure. Results showed that HS-induced lethality and hypothermia were significantly alleviated by ALA treatment that also improved plasma levels of CRE, LDH, and CPK and myocardial injury biomarkers myoglobin and troponin. In addition, ALA reduced cardiac superoxide anion formation and protein expression of cleaved caspase 3 caused by HS. Proinflammatory cytokine TNF-α and NF-κB pathways were significantly reduced by ALA treatment which may be associated with the upregulation of Hsp70. ALA significantly increased the Atg5-12 complex and LC3B II/LC3B I ratio, whereas the p62 and p-mTOR expression was attenuated in HS rats, indicating the activation of autophagy by ALA. In conclusion, ALA ameliorated the deleterious effects of HS by exerting antioxidative and anti-inflammatory capacities. Induction of Hsp70 and activation of autophagy contribute to the protective effects of ALA in HS-induced myocardial injury.
Highlights
With climate change, including in some extreme temperatures, such as heat, the growing incidences of heat-related death have been frequently addressed in recent years [1, 2]
After anesthesia and left femoral arterial and venous cannulation, the rats were randomized into four groups as indicated in Figure 1: (I) normothermal control group (Con): rats were arranged in a heating chamber at room temperature (24°C) for 1 h and maintained throughout the entire experiment (N = 5); (II) Heat stroke (HS) group: rats were placed in a heating chamber (42°C) for 40 min until the rectal core temperature (Tco) elevated to 42°C to induce HS, as previously described [21] (N = 19); (III) ALA40+HS group: HS rats were pretreated with Alpha-lipoic acid (ALA) 40 mg/kg (i.p.)
To further elucidate the relationship between the protective effect of ALA and autophagy, we evaluated the expression levels of autophagyrelated protein 5-12 (Atg5-12), light chain 3 B (LC3B), p62/SQSTM1 (p62), and the phosphorylated mammalian target of rapamycin (p-mTOR), which have been recognized as autophagyassociated markers [11]
Summary
With climate change, including in some extreme temperatures, such as heat, the growing incidences of heat-related death have been frequently addressed in recent years [1, 2]. The pathogenesis of tissue injury in HS is closely mimicked by the mechanism of sepsis [4], which arises from impaired intestinal mucosal barrier and causes translocation of endotoxins [5]. This change allows the secretion of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and eventually triggers systemic inflammation [6]. Heat shock proteins (Hsps) function as molecular chaperones by facilitating the proper folding of proteins to the native conformation and targeting for lysosomal degradation under stress conditions [8] Among these Hsps, Hsp is one of the most extensively studied proteins induced by an increase in temperature of mammalians. The induction of Hsp may be a potential strategy for the treatment of HSinduced cardiomyocyte injury
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