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

Goncharov, Dmitry A.; Kudryashova, Tatiana V.; Ziai, Houman; Ihida-Stansbury, Kaori; DeLisser, Horace M.; Krymskaya, Vera P.; Tuder, Rubin M.; Kawut, Steven M.; Goncharova, Elena A.

doi:10.1161/circulationaha.113.004581

Cited by 171 publications

(271 citation statements)

References 50 publications

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“…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).…”

Section: Discussionmentioning

confidence: 97%

miR-223 reverses experimental pulmonary arterial hypertension

Meloche

Guen

Potus

et al. 2015

American Journal of Physiology-Cell Physiology

107

111

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nary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. It was recently shown that DNA damage could trigger this phenotype by upregulating poly(ADP-ribose)polymerase 1 (PARP-1) expression, although the exact mechanism remains unclear. In silico analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH. We provide evidence that miR-223 is downregulated in human PAH lungs, distal PAs, and isolated PASMCs. Furthermore, using a gain and loss of function approach, we showed that increased hypoxia-inducible factor 1␣, which is observed in PAH, triggers this decrease in miR-223 expression and subsequent overexpression of PARP-1 allowing PAH-PASMC proliferation and resistance to apoptosis. Finally, we demonstrated that restoring the expression of miR-223 in lungs of rats with monocrotaline-induced PAH reversed established PAH and provided beneficial effects on vascular remodeling, pulmonary resistance, right ventricle hypertrophy, and survival. We provide evidence that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH. miR-223; pulmonary hypertension; PARP-1; HIF-1␣; DNA damage PULMONARY ARTERIAL HYPERTENSION (PAH) is a serious condition characterized by obstruction of the precapillary pulmonary arterioles (PA) due to excessive vasoconstriction, inflammation, and imbalance between cells' proliferation and apoptosis within the arterial wall. This remodeling and obstruction of the PAs leads to increases in pulmonary vascular resistance, right ventricular (RV) failure, and death of patients. Despite recent therapeutic advances, most patients exhibit persistently poor exercise capacity and quality of life, with a 3-yr survival rate of 65% (12).Growing evidence underlines the importance of DNA damage in PAH etiology (9,19,23). Indeed, the sustained inflammation, RAGE expression (21), and metabolic stress (30) observed in PAH result in DNA damage-dependent activation of poly(ADP-ribose)polymerase 1 (PARP-1) in PA smooth muscle cells (PASMCs) of PAH patients (23). We recently showed that PARP-1 overexpression was responsible for enhanced PAH-PASMC proliferation and suppressed apoptosis (23). Nevertheless, the mechanisms that regulate this overexpression in PAH remain elusive.In cancer, PARP-1 expression is regulated by microRNA-223 (miR-223), a microRNA involved in DNA damage response (34). According to TargetScan 6.2, PARP-1 is in fact a predicted target of miR-223. Moreover, downregulation of miR-223 has been shown to mediate mechanical stretch-stimulated proliferation of vascular smooth muscle cells (33). Interestingly, Wang et al. (38) reported that miR-...

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Section: Discussionmentioning

confidence: 97%

miR-223 reverses experimental pulmonary arterial hypertension

Meloche

Guen

Potus

et al. 2015

American Journal of Physiology-Cell Physiology

107

111

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“…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.…”

Section: Discussionmentioning

confidence: 99%

mTOR pathway activation drives lung cell senescence and emphysema

et al. 2018

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“…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).…”

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confidence: 99%

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

Kudryashova

Goncharov

Pena

et al. 2016

Am J Respir Crit Care Med

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107

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Rationale: Enhanced proliferation and impaired apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiologic components of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH).Objectives: To determine the role and therapeutic relevance of HIPPO signaling in PAVSMC proliferation/apoptosis imbalance in PAH.Methods: Primary distal PAVSMCs, lung tissue sections from unused donor (control) and idiopathic PAH lungs, and rat and mouse models of SU5416/hypoxia-induced pulmonary hypertension (PH) were used. Immunohistochemical, immunocytochemical, and immunoblot analyses and transfection, infection, DNA synthesis, apoptosis, migration, cell count, and protein activity assays were performed in this study. Measurements and Main Results:Immunohistochemical and immunoblot analyses demonstrated that the HIPPO central component large tumor suppressor 1 (LATS1) is inactivated in small remodeled pulmonary arteries (PAs) and distal PAVSMCs in idiopathic PAH. Molecular-and pharmacology-based analyses revealed that LATS1 inactivation and consequent up-regulation of its reciprocal effector Yes-associated protein (Yap) were required for activation of mammalian target of rapamycin (mTOR)-Akt, accumulation of HIF1a, Notch3 intracellular domain and b-catenin, deficiency of proapoptotic Bim, increased proliferation, and survival of human PAH PAVSMCs. LATS1 inactivation and up-regulation of Yap increased production and secretion of fibronectin that upregulated integrin-linked kinase 1 (ILK1). ILK1 supported LATS1 inactivation, and its inhibition reactivated LATS1, down-regulated Yap, suppressed proliferation, and promoted apoptosis in PAH, but not control PAVSMCs. PAVSM in small remodeled PAs from rats and mice with SU5416/hypoxia-induced PH showed downregulation of LATS1 and overexpression of ILK1. Treatment of mice with selective ILK inhibitor Cpd22 at Days 22-35 of SU5416/hypoxia exposure restored LATS1 signaling and reduced established pulmonary vascular remodeling and PH.Conclusions: These data report inactivation of HIPPO/LATS1, self-supported via Yap-fibronectin-ILK1 signaling loop, as a novel mechanism of self-sustaining proliferation and apoptosis resistance of PAVSMCs in PAH and suggest a new potential target for therapeutic intervention.

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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

Cited by 171 publications

References 50 publications

miR-223 reverses experimental pulmonary arterial hypertension

miR-223 reverses experimental pulmonary arterial hypertension

mTOR pathway activation drives lung cell senescence and emphysema

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

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