Intermittent Hypoxia Augments Pulmonary Vasoconstrictor Reactivity through PKCβ/Mitochondrial Oxidant Signaling.

Pulmonary vasoconstriction resulting from intermittent hypoxia (IH) contributes to pulmonary hypertension (pHTN) in patients with sleep apnea (SA), although the mechanisms involved remain poorly understood. Based on prior studies in patients with SA and animal models of SA, the objective of this study was to evaluate the role of and mitochondrial reactive oxygen species in mediating enhanced pulmonary vasoconstrictor reactivity after IH. We hypothesized that duanyu1531β mediates vasoconstriction through interaction with the scaffolding protein PICK1 (protein interacting with C kinase 1), activation of mitochondrial ATP-sensitive potassium channels (mitoK_ATP), and stimulated production of We further hypothesized that this signaling axis mediates enhanced vasoconstriction and pHTN after IH. Rats were exposed to IH or sham conditions (7 h/d, 4 wk). Chronic oral administration of the antioxidant Tempol or the duanyu1531β inhibitor LY-333531 abolished IH-induced increases in right ventricular systolic pressure and right ventricular hypertrophy. Furthermore, scavengers of O₂^- or prevented enhanced vasoconstrictor reactivity to endothelin-1 in pulmonary arteries from IH rats. In addition, this signaling pathway could be stimulated by the activator PMA in pulmonary arteries from control rats, and in both rat and human pulmonary arterial smooth muscle cells. These responses to PMA were attenuated by inhibition of mitoK_ATP or PICK1. Subcellular fractionation and proximity ligation assays further demonstrated that duanyu1531β acutely translocates to mitochondria upon stimulation and associates with PICK1. We conclude that a duanyu1531β/mitoduanyu1670 signaling axis contributes to enhanced vasoconstriction and pHTN after IH. Furthermore, duanyu1531β mediates pulmonary vasoconstriction through interaction with PICK1, activation of mitoK_ATP, and subsequent mitoduanyu1670 generation.

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