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 PKC beta and mitochondrial reactive oxygen species (mitoROS) in mediating enhanced pulmonary vasoconstrictor reactivity after IH. We hypothesized that PKC beta mediates vasoconstriction through interaction with the scaffolding protein PICKI (protein interacting with C kinase 1), activation of mitochondrial ATP-sensitive potassium channels (mitoK(ATP)), and stimulated production of mitoROS. 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 Tempo) or the PKC beta inhibitor LY-333531 abolished IH-induced increases in right ventricular systolic pressure and right ventricular hypertrophy. Furthermore, scavengers of O-2(-) or mitoROS prevented enhanced PKC beta-dependent vasoconstrictor reactivity to endothelin-1 in pulmonary arteries from IH rats. In addition, this PKC beta/mitoROS signaling pathway could be stimulated by the PKC 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 AT p or PICK1. Subcellular fractionation and proximity ligation assays further demonstrated that PKC beta acutely translocates to mitochondria upon stimulation and associates with PICK1. We conclude that a PKC beta/mitoROS signaling axis contributes to enhanced vasoconstriction and pHTN after IH. Furthermore, PKC beta mediates pulmonary vasoconstriction through interaction with PICK1, activation of mitoK(ATP), and subsequent mitoROS generation.