HSP70-mediated neuroprotection by combined treatment of valproic acid with hypothermia in a rat asphyxial cardiac arrest model

Abstract

It has been reported that valproic acid (VPA) combined with therapeutic hypothermia can improve survival and neurologic outcomes in a rat asphyxial cardiac arrest model. However, neuroprotective mechanisms of such combined treatment of valproic acid with hypothermia remains unclear. We hypothesized that epigenetic regulation of HSP70 by histone acetylation could increase HSP70-mediated neuroprotection suppressed under hypothermia. Male Sprague-Dawley rats that achieved return of spontaneous circulation (ROSC) from asphyxial cardiac arrest were randomized to four groups: normothermia (37°C ± 1°C), hypothermia (33°C ± 1°C), normothermia + VPA (300 mg/kg IV initiated 5 minutes post-ROSC and infused over 20 min), and hypothermia + VPA. Three hours after ROSC, acetyl-histone H3 was highly expressed in VPA-administered groups (normothermia + VPA, hypothermia + VPA). Four hours after ROSC, HSP70 mRNA expression levels were significantly higher in normothermic groups (normothermia, normothermia + VPA) than in hypothermic groups (hypothermia, hypothermia + VPA). The hypothermia + VPA group showed significantly higher HSP70 mRNA expression than the hypothermia group. Similarly, at five hours after ROSC, HSP70 protein levels were significantly higher in normothermic groups than in hypothermic groups. HSP70 levels were significantly higher in the hypothermia + VPA group than in the hypothermia group. Only the hypothermia + VPA group showed significantly attenuated cleaved caspase-9 levels than the normothermia group. Hypothermia can attenuate the expression of HSP70 at transcriptional level. However, VPA administration can induce hyperacetylation of histone H3, leading to epigenetic transcriptional activation of HSP70 even in a hypothermic status. Combining VPA treatment with hypothermia may compensate for reduced activation of HSP70-mediated anti-apoptotic pathway.

Advanced Diagnostic Tools in Hypothermia-Related Fatalities—A Pathological Perspective

“…The cellular response to heat-induced stress is also manifested by an increased expression of heat shock proteins (Hsps) or chaperones. Among these, Hsp70 and Hsp90 display a neuroprotection effect in ischemic stroke models [12,14]. Although studies focusing on the link between hypothermia and chaperone expression are relatively limited, molecular tests showed that Hsp70 overexpression is associated with increased neuronal resistance and faster regeneration following hypoxia-induced cerebral cortical injuries [23].…”

“…Its role in cerebral protection and postlesional repair has recently been recognized, being recommended as one of the most specific astrocyte markers according to investigations of its association with depression, brain trauma, thermal stress, and neurodegenerative diseases, e.g., Alzheimer's disease [7,10,11]. Ischemia and hypothermic stress may lead to a heat-shock-like response [12]. As a central component of chaperons' intracellular network, heat shock protein 70 (Hsp70) is a neuroprotective factor involved in assisting protein folding, translocation, and degradation [13,14].…”

“…As a central component of chaperons' intracellular network, heat shock protein 70 (Hsp70) is a neuroprotective factor involved in assisting protein folding, translocation, and degradation [13,14]. Postmortem studies have revealed the induction of Hsp70 expression in the human brain when exposed to low-temperature conditions, representing an indicator of cellular stress [12,15].…”

Cellular protection from H2O2toxicity by Fv-Hsp70. Protection via catalase and gamma-glutamyl cysteine synthase

“…Hypothermia was shown to be neuroprotective in neonatal hypoxic injury (Azzopardi 2014). An animal study showed that Hsp70 combined with valproic acid (HDAC inhibitor) and therapeutic hypothermia resulted in neuroprotection in a rat asphyxial cardiac arrest model (Oh et al 2021). In human adults there is controversy with both positive and negative outcomes with moderate hypothermia.…”

Cellular protection from H2O2 toxicity by Fv-Hsp70: protection via catalase and gamma-glutamyl-cysteine synthase

“…Hypothermia was shown to be neuroprotective in neonatal hypoxic injury (Azzopardi et al 2014 ). An animal study showed that Hsp70 combined with valproic acid (HDAC inhibitor) and therapeutic hypothermia resulted in neuroprotection in a rat asphyxia cardiac arrest model (Oh et al 2021 ). In human adults, there is controversy with both positive and negative outcomes with moderate hypothermia.…”