Hypoxia‐Induced Pulmonary Hypertension: Possible Loss of Caveolin‐1 Function

Abstract

We have previously shown an early and progressive IL-6 mRNA upregulation, IL-6 bioactivity, loss of endothelial caveolin-1 and reciprocal activation of PY-STAT3, and subsequent loss of HSP90 and eNOS in an inflammatory (monocrotaline, MCT) model of pulmonary hypertension (PH) in rats. Furthermore, rescue of caveolin-1 inhibits PY-STAT3 activation and attenuates MCT-induced PH. Since hypoxia also elicits an inflammatory response, we investigated time-dependent alterations in the expression of caveolin-1, PY-STAT3, eNOS and HSP90 during hypoxia-induced PH. Male Sprague-Dawley rats were subjected to hypobaric hypoxia and examined at 48h, 1 and 2 weeks of hypoxia. Significant PH was noted at 1 and 2 wks, and RVH at 2 wks of hypoxia. PY-STAT3 activation was observed at 48 hrs before the onset of PH, which was persistent, but there was no loss of caveolin-1 expression during hypoxia. Expression of eNOS was significantly increased during hypoxia; however the p-eNOS was decreased at 2 wks after a slight increase at 48h and 1 wk of hypoxia. HSP90 expression was unaltered. Caveolin-1 is known to inhibit PY-STAT3 activation and modulate eNOS activation. These results suggest that caveolin-1 dysfunction may play a significant role in hypoxia-induced PH.