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Mammalian Target of Rapamycin Complex 2 (mTORC2) Coordinates Pulmonary Artery Smooth Muscle Cell Metabolism, Proliferation, and Survival in Pulmonary Arterial Hypertension Hypertension

protein Bim and idiopathic PAH PAVSMC survival. NADPH oxidase 4 (Nox4) protein levels were increased in idiopathic PAH PAVSMCs, which was necessary for mTORC2 activation, proliferation, and survival. Nox4 levels and mTORC2 signaling were significantly upregulated in small pulmonary arteries from hypoxia-exposed rats at days 2 to 28 of hypoxia. Treatment with the mTOR kinase inhibitor PP242 at days 15 to 28 suppressed mTORC2 but not Nox4, induced smooth muscle–specific apoptosis in small pulmonary arteries, and reversed hypoxia-induced pulmonary vascular remodeling in rats. Conclusions —These data provide a novel mechanistic link of Nox4-dependent activation of mTORC2 via the energy sensor AMP-activated protein kinase to increased proliferation and survival of PAVSMCs in PAH, which suggests a new potential pathway for therapeutic interventions. ( Circulation . 2014;129:864-874.) both and pathways are in small remodeled pulmonary and primary distal PAVSMCs from subjects with and and Using molecular and pharmacology-based analyses, we demonstrate a novel mechanistic link from NADPH oxidase Nox4-dependent activation of mTORC2 via energy sensor AMP-activated protein kinase (AMPK) to the activation of mTORC1 and increased proliferation, as well as deficiency of proapoptotic Bim and IPAH PAVSMC survival. We also provide evidence that in contrast to the mTORC1 inhibitor rapamycin, the dual mTORC1/ mTORC2 inhibitor PP242 not only inhibits proliferation but also induces apoptosis in PAVSMCs from IPAH patients without a significant effect on control cells. Treatment with PP242 induces apoptosis in small pulmonary arteries and reverses existing pulmonary vascular remodeling in the rat chronic hypoxia model of pulmonary hypertension. These data suggest a novel role for mTORC2 in pulmonary vascular remodeling and provide a new potential target pathway for therapeutic interventions for this incurable disease.