A new mechanism of high-altitude adaptation reducing myocardium infarction: inhibiting inflammation-induced ubiquitin degradation of BK to enhance coronary vasodilation.

Our prior research demonstrated that chronic intermittent hypobaric hypoxia (CIHH) pretreatment confers cardioprotection against ischemia/reperfusion (I/R) injury in rats. However, the precise mechanisms underlying CIHH's cardioprotective effects remain insufficiently understood. This study aims to elucidate the upstream signaling pathways and dynamic regulation of BK channels in mediating CIHH-induced cardioprotection through coronary artery vasodilation in rats. Male Sprague-Dawley rats, matched by age and body weight, were assigned to control (Con) and CIHH groups. The CIHH group underwent 35 days of hypobaric hypoxia exposure simulating an altitude of 4000 m, for 5 h daily. Hearts were isolated, perfused using the Langendorff system, and subjected to 30 min of ischemia, followed by 60 or 120 min of reperfusion. Compared to the Con group, CIHH significantly improved left ventricular function recovery, reduced infarct size, and increased coronary flow (CF). Microvessel recording, co-immunoprecipitation, and whole-cell patch clamp techniques demonstrated that CIHH augmented CF by promoting coronary vasodilation, attributed to the inhibition of muscle RING-finger protein-1 (MuRF1)-mediated degradation of the BK-β subunit. Moreover, CIHH inhibited IKKα-induced phosphorylation and ubiquitin-mediated degradation of IκBα, thereby enhancing its cytoplasmic binding to NF-κB p65 in coronary smooth muscle cells. This process attenuated NF-κB p65 nuclear translocation and the subsequent inflammation-induced expression of MuRF1. The observed increase in coronary vasodilation, driven by the suppression of NF-κB/MuRF1-mediated BK-β degradation, contributes to enhanced CF and cardioprotection against I/R injury following CIHH.