Hypoxia Increases Cardiac Proteasomal Activity and Differentially Modulates Cullin-RING E3 Ligases in the Naked Mole-Rat <i>Heterocephalus glaber</i>.

(1) Background: The naked mole-rat (<i>Heterocephalus glaber</i>) survives hypoxia-reoxygenation stresses by utilizing metabolic rate depression, achieved in part by downregulating nonessential genes and processes to conserve endogenous cellular resources and prevent buildup of toxic waste byproducts. Tight molecular control of protein degradation (specifically the ubiquitin-proteasome system) is a potent regulatory tool for maintaining muscle integrity during hypoxia, but how this system is regulated in the heart of hypoxia-tolerant species is poorly understood. (2) Methods: The protein expression levels of cullin-RING E3 ligases (specifically CRL4 architecture), deubiquitinating enzymes, and proteasomal activity were assayed in cardiac tissues from <i>H. glaber</i> exposed to 24 h of normoxia or hypoxia in vivo. (3) Results: Overall, the protein expression of E3 ligases decreased, whereas expression of deubiquitinating enzymes increased during hypoxia, all of which play roles in themes of oxidative stress, heightened DNA damage repair, and the HIF-1-VHL-NFκB axis. Proteasomal activity was elevated during hypoxia, which conceivably links to the oxidative stress theory of aging and longevity of <i>H. glaber</i>. (4) Conclusions: Taken together, our results expand current research into protein degradation and extreme environmental stress responses, with a specific focus on cardiac mechanisms related to oxidative stress resistance along the hypoxia-longevity axis.