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

• Published in: Circulation (New York, N.Y.) Vol. 129; no. 8; pp. 864 - 874
• Main Authors: Goncharov, Dmitry A., Kudryashova, Tatiana V., Ziai, Houman, Ihida-Stansbury, Kaori, DeLisser, Horace, Krymskaya, Vera P., Tuder, Rubin M., Kawut, Steven M., Goncharova, Elena A.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD by the American College of Cardiology Foundation and the American Heart Association, Inc 25.02.2014; Lippincott Williams & Wilkins
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Carrier Proteins - metabolism; Cell Proliferation; Cell Survival - physiology; Cells, Cultured; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Energy Metabolism - physiology; Familial Primary Pulmonary Hypertension; Female; Glycolysis - physiology; Humans; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; Hypoxia - metabolism; Hypoxia - pathology; Male; Mechanistic Target of Rapamycin Complex 2; Medical sciences; Multiprotein Complexes - metabolism; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Pharmacology. Drug treatments; Pneumology; Pulmonary Artery - cytology; Pulmonary Artery - metabolism; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Rapamycin-Insensitive Companion of mTOR Protein; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; TOR Serine-Threonine Kinases - metabolism; Antineoplastic agent; Cell proliferation; Energy metabolism; remodeling; Prognosis; Sirolimus; Non-specific serine/threonine protein kinase; muscle, smooth, vascular; Smooth muscle; Cardiovascular disease; AMP-activated protein kinase; Macrocycle; Complexity; Vascular remodeling; Signal transduction; Target; Pulmonary vessel; Blood vessel; Protein synthesis inhibitor; Cardiology; AMP; Enzyme; Respiratory disease; Transferases; Idiopathic; Lactone; Macrolide; Complexes; Survival; Pulmonary artery; Pulmonary hypertension; idiopathic pulmonary arterial hypertension; Vertebrata; Antibiotic; Mammalia; Coordinate; Circulatory system; Immunosuppressive agent; Antibacterial agent; mTORC2; signal transduction; energy metabolism
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.113.004581

BACKGROUND—Enhanced proliferation, resistance to apoptosis, and metabolic shift to glycolysis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiological components of pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (PAH). The role of the distinct mammalian target of rapamycin (mTOR) complexes mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor) in PAVSMC proliferation and survival in PAH and their therapeutic relevance are unknown. METHODS AND RESULTS—Immunohistochemical and immunoblot analyses revealed that mTORC1 and mTORC2 pathways are markedly upregulated in small remodeled pulmonary arteries and isolated distal PAVSMCs from subjects with idiopathic PAH that have increased ATP levels, proliferation, and survival that depend on glycolytic metabolism. Small interfering RNA– and pharmacology-based analysis showed that although both mTORC1 and mTORC2 contribute to proliferation, only mTORC2 is required for ATP generation and survival of idiopathic PAH PAVSMCs. mTORC2 downregulated the energy sensor AMP-activated protein kinase, which led to activation of mTORC1-S6 and increased proliferation, as well as a deficiency of the proapoptotic 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.