Heat shock protein 70 and AMP‐activated protein kinase contribute to 17‐DMAG‐dependent protection against heat stroke

Abstract

Heat shock protein 70 (Hsp70) preconditioning induces thermotolerance, and adenosine monophosphate (AMP)‐activated protein kinase (AMPK) plays a role in the process of autophagy. Here, we investigated whether 17‐dimethylaminoethylamino‐17‐demethoxy‐geldanamycin (17‐DMAG) protected against heat stroke (HS) in rats by up‐regulation of Hsp70 and phosphorylated AMPK (pAMPK). To produce HS, male Sprague–Dawley rats were placed in a chamber with an ambient temperature of 42°C. Physiological function (mean arterial pressure, heart rate and core temperature), hepatic and intestinal injury, inflammatory mediators and levels of Hsp70, pAMPK and light chain 3 (LC3B) in hepatic tissue were measured in HS rats or/and rats pre‐treated with 17‐DMAG. 17‐DMAG pre‐treatment significantly attenuated hypotension and organ dysfunction induced by HS in rats. The survival time during HS was also prolonged by 17‐DMAG treatment. Hsp70 expression was increased, whereas pAMPK levels in the liver were significantly decreased in HS rats. Following pre‐treatment with 17‐DMAG, Hsp70 protein levels increased further, and pAMPK levels were enhanced. Treatment with an AMPK activator significantly increased the LC3BII/LC3BI ratio as a marker of autophagy in HS rats. Treatment with quercetin significantly suppressed Hsp70 and pAMPK levels and reduced the protective effects of 17‐DMAG in HS rats. Both of Hsp70 and AMPK are involved in the 17‐DMAG‐mediated protection against HS. 17‐DMAG may be a promising candidate drug in the clinical setting.

Activation of autophagy is involved in the protective effect of 17β‐oestradiol on endotoxaemia‐induced multiple organ dysfunction in ovariectomized rats

“…Recently, it has been shown in mice that HO‐1‐mediated autophagy protects against hepatocyte cell death and hepatic injury from infection/sepsis . Furthermore, HSP70 has been suggested to activate the autophagic process to protect against heat‐shock stress . In this study, we demonstrated that oestrogen can preserve the capacity of cellular HO‐1 and HSP70 production during endotoxaemia (Fig.…”

“…It is worth noting that in mice, the antioxidant enzyme HO‐1‐mediated autophagy protects against hepatocyte cell death and hepatic injury from infection/sepsis . Our previous report revealed that up‐regulation of HSP 70 is associated with activation of autophagy, leading to protection against heat stress . Therefore, in this study, we evaluated the preventive effect of long‐term E 2 replacement on endotoxaemia‐induced septic shock and MODS, such as hepatic and renal dysfunction, rhabdomyolysis and coagulopathy in anaesthetized Ovx rats and further investigated whether activation of autophagy, as well as induction of HO‐1 and HSP70 contribute to the beneficial effects of oestrogen.…”

Alpha-Lipoic Acid Protects Cardiomyocytes against Heat Stroke-Induced Apoptosis and Inflammatory Responses Associated with the Induction of Hsp70 and Activation of Autophagy

“…After anesthesia (urethane 1.2 g/kg, i.p.) 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) 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 ALA 40 mg/kg (i.p.) (Sigma-Aldrich, St. Louis, MO, USA) at 1.5 h prior to heat stress ( N = 12); (IV) ALA80+HS group: rats were pretreated with ALA 80 mg/kg (i.p.)…”

Heat stroke

“…Heat shock proteins (HSP) are a family of proteins produced by nearly all cells in response to stressful conditions, including heat shock as well as other stresses, such as exposure to cold and ultraviolet light [ 6 , 30 ]. Increased levels of HSPs, such as HSP70, are necessary for acquired heat tolerance.…”

“…Increased levels of HSPs, such as HSP70, are necessary for acquired heat tolerance. Moreover, the overexpression of HSP70 in response to heat stress can protect against organ dysfunction and reduces mortality in rats [ 30 ].…”