A Novel Mechanism for Cross-Adaptation between Heat and Altitude Acclimation: The Role of Heat Shock Protein 90

Abstract

Heat shock protein 90 (HSP90) is a member of a family of molecular chaperone proteins which can be upregulated by various stressors including heat stress leading to increases in HSP90 protein expression. Its primary functions include (1) renaturing and denaturing of damaged proteins caused by heat stress and (2) interacting with client proteins to induce cell signaling for gene expression. The latter function is of interest because, in cancer cells, HSP90 has been reported to interact with the transcription hypoxic-inducible factor 1α(HIF1α). In a normoxic environment, HIF1αis degraded and therefore has limited physiological function. In contrast, in a hypoxic environment, stabilized HIF1αacts to promote erythropoiesis and angiogenesis. Since HSP90 interacts with HIF1α, and HSP90 can be upregulated from heat acclimation in humans, we present a proposal that heat acclimation can mimic molecular adaptations to those of altitude exposure. Specifically, we propose that heat acclimation increases HSP90 which then stabilizes HIF1αin a normoxic environment. This has many implications since HIF1αregulates red blood cell and vasculature formation. In this paper we will discuss (1) the functional roles of HSP90 and HIF1α, (2) the interaction between HSP90 and other client proteins including HIF1α, and (3) results fromin vitrostudies that may suggest how the relationship between HSP90 and HIF1αmight be applied to individuals preparing to make altitude sojourns.

Heat acclimation does not affect maximal aerobic power in thermoneutral normoxic or hypoxic conditions

“…In contrast, HIF‐1α is stimulated by exposure to systemic hypoxia and mediates molecular adaptations to upregulate angiogenesis, erythropoiesis (Goldberg & Schneider, ) and respiration (Wilson, Roy, & Lahiri, ). HSP90 interacts with the oxygen‐dependent HIF‐1α subunit, stabilizing HIF‐1α even in normoxic conditions (Salgado, White, Schneider, & Mermier, ). Other physiological adaptations underlying HA at a systemic level may be secondary to the expanded plasma volume (PV) and include improved exercise economy (Sawka, Pandolf, Avellini, & Shapiro, ), greater stroke volume (SV), lower heart rate (HR) (Lorenzo, Halliwill, Sawka, & Minson, ), and increased ventricular compliance and myocardial efficiency (Horowitz, Shimoni, Parnes, Gotsman, & Hasin, ).…”

“…1994) and respiration (Wilson, Roy, & Lahiri, 2005). HSP90 interacts with the oxygen-dependent HIF-1 subunit, stabilizing HIF-1 even in normoxic conditions (Salgado, White, Schneider, & Mermier, 2014).…”

Heat acclimation attenuates physiological strain and the HSP72, but not HSP90α, mRNA response to acute normobaric hypoxia

“…Heat acclimation (HA), and acclimatization interventions, carried out by repeated exercise in hot conditions (58), reproducibly reduce physiological strain in hot and cooler conditions (32,33,39). Recent reviews support a novel adaptive pathway whereby HA may reduce physiological strain in hypoxia (14,56,73). Mechanistic pathways can be subdivided into crossacclimation, whereby HA attenuates physiological strain (73) and cross-tolerance, whereby cellular responses to HA provide cytoprotection during hypoxia (14).…”

Heat acclimation and cross tolerance to hypoxia

“…Hot and hypoxic cross-tolerance has been a subject of recent interest for military personnel and/or athletes who work or compete in both hot and high-altitude environments. 4 , 5 However, the link between the observed cellular cross-tolerance and systemic acclimatory responses to hot or hypoxic environments has not been fully elucidated. Currently, cross-tolerance is primarily attributed to changes at the cellular level.…”