Caveolin‐1 suppresses hippocampal neuron apoptosis via the regulation of HIF1α in hypoxia in naked mole‐rats

Abstract

Naked mole-rats (NMRs) (Heterocephalus glaber) are highly social and subterranean rodents with large communal colonies in burrows containing low oxygen levels. The inhibition of severe hypoxic conditions is of particular interest to this study. To understand the mechanisms that facilitate neuronal preservation during hypoxia, we investigated the proteins regulating hypoxia tolerance in NMR hippocampal neurons. Caveolin-1 (Cav-1), a transmembrane scaffolding protein, confers prosurvival signalling in the central nervous system. The present study aimed to investigate the role of Cav-1 in hypoxia-induced neuronal injury. Western blotting analysis and immunocytochemistry showed that Cav-1 expression was significantly upregulated in NMR hippocampal neurons under 8% O 2 conditions for 8 h. Cav-1 alleviates apoptotic neuronal death from hypoxia. Downregulation of Cav-1 by lentiviral vectors suggested damage to NMR hippocampal neurons under hypoxic conditions in vitro and in vivo. Overexpression of Cav-1 by LV-Cav-1 enhanced hypoxic tolerance of NMR hippocampal neurons in vitro and in vivo. Mechanistically, the levels of hypoxia inducible factor-1α (HIF-1α) are also increased under hypoxic conditions. After inhibiting the binding of HIF-1α to hypoxia response elements in the DNA by echinomycin, Cav-1 levels were downregulated significantly. Furthermore, chromatin immunoprecipitation assays showed the direct role of HIF1α in regulating the expression levels of Cav-1 in NMR hippocampal neurons under hypoxic conditions. These findings suggest that Cav-1 plays a critical role in modulating the apoptosis of NMR hippocampal neurons and warrant further studies targeting Cav-1 to treat hypoxia-associated brain diseases.

Caveolin-1 scaffolding domain-derived peptide enhances the antiapoptotic progresses of corpus cavernosum smooth muscle cells after cavernous nerve injury

“…Further evidence for CAV1's involvement in limiting ROS production was provided by Chen et al [33]. Similar to how it does in sepsis, hepatic ischemia and reperfusion injury, hypoxia-induced neuronal injury, and acetaminopheninduced cardiovascular injury, CAV1 likewise functions as a brake on apoptosis and ROS [18][19][20][21][22]. It has been demonstrated that CSD peptide, which is derived from CAV1 protein, can be an equivalence to CAV1 and thereby block apoptosis triggered by TGF-β1, hypoxia, or bleomycin [22,[24][25][26].…”

“…Caveolin-1 (CAV1) is an integral membrane protein that serves as the structural basis for caveolae [15]. It is extensively expressed in numerous cells and tissues, and has been implicated in the mitigation of apoptosis through the regulation and control of TGF-β1 signaling, cellular response to hypoxia, in ammation, and oxidative stress [16][17][18][19][20][21][22]. CAV1 expression and α-SMA-positive staining were observed to be signi cantly reduced in cavernous smooth muscle tissue of CNI rats, whereas supplementation of sildena l could mediate the restoration of smooth muscle content by facilitating the regeneration of CAV1 [23].…”