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

Abstract

Background Enhanced proliferation, resistance to apoptosis and metabolic shift to glycolysis of pulmonary arterial vascular smooth muscle cells (PAVSMC) are key pathophysiological components of pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH). The role of distinct mTOR complexes mTORC1 (mTOR-raptor) and mTORC2 (mTOR-rictor) in PAVSMC proliferation and survival in PAH and their therapeutic relevance is unknown. Methods and Results Immunohistochemical and immunoblot analyses revealed that mTORC1 and mTORC2 pathways are markedly up-regulated in small remodeled PAs and isolated distal PAVSMC from IPAH subjects that have increased ATP levels, proliferation and survival that depend on glycolytic metabolism. siRNA- and pharmacological-based analysis showed that while both mTORC1 and mTORC2 contributing to proliferation, only mTORC2 is required for ATP generation and survival of IPAH PAVSMC. mTORC2 down-regulated energy sensor AMPK allowing activation of mTORC1-S6 and increased proliferation, and deficiency of pro-apoptotic protein Bim and IPAH PAVSMC survival. Nox4 protein levels were increased in IPAH PAVSMC that was necessary for mTORC2 activation, proliferation and survival. Nox4 levels and mTORC2 signaling were significantly up-regulated in small PAs from hypoxia-exposed rats at days 2-28 of hypoxia. Treatment with the mTOR kinase inhibitor PP242 at days 15-28 suppressed mTORC2, but not Nox4, induced SM-specific apoptosis in small PAs and reversed hypoxia-induced pulmonary vascular remodeling in rats. Conclusions These data provide a novel mechanistic link of Nox4-dependent activation of mTORC2 via energy sensor AMPK to increased proliferation and survival of PAVSMC in PAH suggesting a new potential pathway for the therapeutic interventions.

miR-223 reverses experimental pulmonary arterial hypertension

“…Thus, we could also speculate that miR-223 downregulation can also lead to increased KLF5 expression observed in PAH (8). Moreover, downstream miR-223 targets IGF-1R and HSP90␤ seem to act on proliferation through the phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin (PI3K/Akt/ mTOR) pathway (13,18) known to play a role in PAH pathophysiology (10,26,36).…”

mTOR pathway activation drives lung cell senescence and emphysema

“…Activation of mTOR contributes to proliferative lung diseases such as lung cancer and pulmonary hypertension (28)(29)(30)(31), but its potential involvement in degenerative lung diseases such as COPD has not been specifically investigated. Our evidence of mTOR overactivity and increased cell senescence in COPD, combined with the efficacy of rapamycin in decreasing both mTOR activity and cell senescence, point to mTOR activation as a major driver of cell senescence in lungs from patients with COPD.…”

HIPPO–Integrin-linked Kinase Cross-Talk Controls Self-Sustaining Proliferation and Survival in Pulmonary Hypertension

“…Increased proliferation and impaired apoptosis of vascular cells in small PAs are key components of pulmonary vascular remodeling in PAH (3,5). Distal pulmonary arterial vascular smooth muscle cells (PAVSMCs) in PAH undergo complex signaling reprogramming resulting in loss of growth suppressors, persistent activation of proproliferative/prosurvival pathways, and acquisition of unique disease-specific phenotype with intrinsic proliferative/prosurvival potential (5-7).…”