MicroRNA‑15a‑5p induces pulmonary artery smooth muscle cell apoptosis in a pulmonary arterial hypertension model via the VEGF/p38/MMP‑2 signaling pathway

Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is a critical pathological feature in the pathogenesis of pulmonary arterial hypertension (PAH), but the regulatory mechanisms remain largely unknown. Herein, we demonstrated that interferon regulatory factor 9 (IRF9) accelerated PASMCs proliferation by regulating Prohibitin 1 (PHB1) expression and the AKT-GSK3β signaling pathway. Compared with control groups, the rats treated with chronic hypoxia (CH), monocrotaline (MCT) or sugen5416 combined with chronic hypoxia (SuHx), and mice challenged with CH had significantly thickened pulmonary arterioles and hyperproliferative PASMCs. More importantly, the protein level of IRF9 was found to be elevated in the thickened medial wall of the pulmonary arterioles in all of these PAH models. Notably, overexpression of IRF9 significantly promoted the proliferation of rat and human PASMCs, as evidenced by increased cell counts, EdU-positive cells and upregulated biomarkers of cell proliferation. In contrast, knockdown of IRF9 suppressed the proliferation of rat and human PASMCs. Mechanistically, IRF9 directly restrained PHB1 expression and interacted with AKT to inhibit the phosphorylation of AKT at thr308 site, which finally led to mitochondrial dysfunction and PASMC proliferation. Unsurprisingly, MK2206, a specific inhibitor of AKT, partially reversed the PASMC proliferation inhibited by IRF9 knockdown. Thus, our results suggested that elevation of IRF9 facilitates PASMC proliferation by regulating PHB1 expression and AKT signaling pathway to affect mitochondrial function during the development of PAH, which indicated that targeting IRF9 may serve as a novel strategy to delay the pathological progression of PAH.

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Insulin Growth Factor-Induced Pulmonary Artery Smooth Muscle Cell Proliferation In Patients With Pulmonary Arterial Hypertension

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a4836 ◽

2012 ◽

Author(s):

Laurence Dewachter ◽

Celine Dewachter ◽

Benoit Rondelet ◽

Myriam Remmelinck ◽

Jean-Luc Vachiery ◽

...

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Growth Factor ◽

Pulmonary Arterial Hypertension ◽

Pulmonary Artery ◽

Arterial Hypertension ◽

Smooth Muscle Cell ◽

Insulin Growth Factor ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle

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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

Circulation ◽

10.1161/circulationaha.113.004581 ◽

2014 ◽

Vol 129 (8) ◽

pp. 864-874 ◽

Cited By ~ 108

Author(s):

Dmitry A. Goncharov ◽

Tatiana V. Kudryashova ◽

Houman Ziai ◽

Kaori Ihida-Stansbury ◽

Horace DeLisser ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Arterial Hypertension ◽

Pulmonary Artery ◽

Arterial Hypertension ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Cell Metabolism ◽

Mammalian Target Of Rapamycin ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle

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PDGF-dependent β-catenin activation is associated with abnormal pulmonary artery smooth muscle cell proliferation in pulmonary arterial hypertension

FEBS Letters ◽

10.1002/1873-3468.12038 ◽

2016 ◽

Vol 590 (1) ◽

pp. 101-109 ◽

Cited By ~ 23

Author(s):

Jack Takahashi ◽

Mark Orcholski ◽

Ke Yuan ◽

Vinicio de Jesus Perez

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Pulmonary Arterial Hypertension ◽

Pulmonary Artery ◽

Arterial Hypertension ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Smooth Muscle Cell Proliferation ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle

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Faculty Opinions recommendation of Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718185664.793499131 ◽

2014 ◽

Author(s):

Vinicio de Jesus Perez

Keyword(s):

Smooth Muscle ◽

Pulmonary Arterial Hypertension ◽

Pulmonary Artery ◽

Arterial Hypertension ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Cell Metabolism ◽

Mammalian Target Of Rapamycin ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle

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Abstract 12714: Aldosterone Activates Raptor to Promote Pulmonary Artery Smooth Muscle Cell Proliferation and Pulmonary Arterial Hypertension

Circulation ◽

10.1161/circ.132.suppl_3.12714 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Thomas E Stephens ◽

Elena Arons ◽

Ying-Yi Zhang ◽

Paula Zaman ◽

Reza Aghamohammadzadeh ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Arterial Hypertension ◽

Pulmonary Artery ◽

Arterial Hypertension ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Vascular Remodeling ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle

In pulmonary arterial hypertension (PAH), elevated levels of aldosterone (ALDO) induce a vasculopathy that is characterized by dysregulated pulmonary artery smooth muscle cell (PSMC) growth. Upregulation of the mammalian target of rapamycin complex 1 subunit Raptor induces PSMC growth; however, the factors regulating Raptor in PAH are not known. We hypothesized that Raptor activation by ALDO induces PSMC proliferation, hypertrophic vascular remodeling, and PAH. To test this hypothesis, PSMCs were exposed to vehicle (V) control or ALDO (10 -7 mol/l) for 1 h. Compared to V-treated cells, ALDO increased expression of P-Raptor(Ser792) and the Raptor target P-p70S6K(Thr389) by 68% (P<0.01) and 50% (P<0.01), respectively, without affecting total Raptor/p70S6K levels. Raptor upregulation in ALDO-treated cells also increased PSMC proliferation by 19% (P<0.01), assessed by BrdU incorporation. To explore the relevance of ALDO-Raptor signaling in vivo , we studied the monocrotaline (MCT) model of PAH, which is characterized by hyperALDO. In a prevention protocol, MCT-PAH rats were treated with spironolactone (SP)(25 mg/kg/d) in the drinking water to inhibit ALDO and/or intravenous Staramine-mPEG labeled with Raptor-siRNA (2 mg/kg dose x4)(si-Raptor). Anti-Raptor and anti-α-SM actin immunohistochemistry showed that compared to controls (N=4), Raptor expression and vessel thickness was increased in MCT-PAH rats (N=5) by 87% (P<0.01) and 5.8-fold (P<0.01), respectively, and pulmonary artery systolic pressure (PASP) was increased significantly (25 ± 4 vs. 77 ± 12 mmHg, P<0.01) as assessed by catheterization. Compared to MCT-PAH, MCT-si-Raptor (N=5) decreased Raptor levels by 31% (P<0.05), arteriole thickness by 41% (P<0.05), and PASP (77 ± 12 vs. 46 ± 5 mmHg, P<0.05) without affecting central blood pressure significantly. A further benefit was observed in MCT-si-Raptor+SP rats (N=5) for arterial thickness (-57%, P<0.01) and PASP (46 ± 5 vs. 39 ± 5 mmHg, P<0.05) compared to MCT-si-Raptor. Taken together, Raptor activation by ALDO induces PSMC proliferation in vitro to promote PAH in vivo . Identifying ALDO-Raptor signaling as a pathobiological mechanism underlying pulmonary vascular remodeling may have novel therapeutic implications for PAH patients.

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