scholarly journals Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Marisela Rodriguez ◽  
Jiyuan Chen ◽  
Pritesh P. Jain ◽  
Aleksandra Babicheva ◽  
Mingmei Xiong ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Calcium Homeostasis ◽  
Vascular Remodeling ◽  
Serum Starvation ◽  
Wall Thickening ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Excessive pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and migration are implicated in the development of pathogenic pulmonary vascular remodeling characterized by concentric arterial wall thickening and arteriole muscularization in patients with pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell contractile-to-proliferative phenotypical transition is a process that promotes pulmonary vascular remodeling. A rise in cytosolic Ca2+ concentration [(Ca2+)cyt] in PASMCs is a trigger for pulmonary vasoconstriction and a stimulus for pulmonary vascular remodeling. Here, we report that the calcium homeostasis modulator (CALHM), a Ca2+ (and ATP) channel that is allosterically regulated by voltage and extracellular Ca2+, is upregulated during the PASMC contractile-to-proliferative phenotypical transition. Protein expression of CALHM1/2 in primary cultured PASMCs in media containing serum and growth factors (proliferative PASMC) was significantly greater than in freshly isolated PA (contractile PASMC) from the same rat. Upregulated CALHM1/2 in proliferative PASMCs were associated with an increased ratio of pAKT/AKT and pmTOR/mTOR and an increased expression of the cell proliferation marker PCNA, whereas serum starvation and rapamycin significantly downregulated CALHM1/2. Furthermore, CALHM1/2 were upregulated in freshly isolated PA from rats with monocrotaline (MCT)-induced PH and in primary cultured PASMC from patients with PAH in comparison to normal controls. Intraperitoneal injection of CGP 37157 (0.6 mg/kg, q8H), a non-selective blocker of CALHM channels, partially reversed established experimental PH. These data suggest that CALHM upregulation is involved in PASMC contractile-to-proliferative phenotypical transition. Ca2+ influx through upregulated CALHM1/2 may play an important role in the transition of sustained vasoconstriction to excessive vascular remodeling in PAH or precapillary PH. Calcium homeostasis modulator could potentially be a target to develop novel therapies for PAH.

scholarly journals Pulmonary Artery Smooth Muscle Cell Senescence Promotes the Proliferation of PASMCs by Paracrine IL-6 in Hypoxia-Induced Pulmonary Hypertension

2021 ◽  
Vol 12 ◽  
Author(s):  
Ai-Ping Wang ◽  
Fang Yang ◽  
Ying Tian ◽  
Jian-Hui Su ◽  
Qing Gu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Remodeling ◽  
Pathophysiological Mechanism ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Artery Smooth Muscle ◽  
Active Substances

Pulmonary hypertension (PH) is a critical and dangerous disease in cardiovascular system. Pulmonary vascular remodeling is an important pathophysiological mechanism for the development of pulmonary arterial hypertension. Pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy, and enhancing secretory activity are the main causes of pulmonary vascular remodeling. Previous studies have proven that various active substances and inflammatory factors, such as interleukin 6 (IL-6), IL-8, chemotactic factor for monocyte 1, etc., are involved in pulmonary vascular remodeling in PH. However, the underlying mechanisms of these active substances to promote the PASMC proliferation remain to be elucidated. In our study, we demonstrated that PASMC senescence, as a physiopathologic mechanism, played an essential role in hypoxia-induced PASMC proliferation. In the progression of PH, senescence PASMCs could contribute to PASMC proliferation via increasing the expression of paracrine IL-6 (senescence-associated secretory phenotype). In addition, we found that activated mTOR/S6K1 pathway can promote PASMC senescence and elevate hypoxia-induced PASMC proliferation. Further study revealed that the activation of mTOR/S6K1 pathway was responsible for senescence PASMCs inducing PASMC proliferation via paracrine IL-6. Targeted inhibition of PASMC senescence could effectively suppress PASMC proliferation and relieve pulmonary vascular remodeling in PH, indicating a potential for the exploration of novel anti-PH strategies.

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

Circulation ◽  
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.

scholarly journals Long Non-Coding RNA MEG3 Downregulation Triggers Human Pulmonary Artery Smooth Muscle Cell Proliferation and Migration via the p53 Signaling Pathway

2017 ◽  
Vol 42 (6) ◽  
pp. 2569-2581 ◽  
Author(s):  
Zengxian Sun ◽  
Xiaowei Nie ◽  
Shuyang Sun ◽  
Shumin Dong ◽  
Chunluan Yuan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Remodeling ◽  
Pulmonary Artery Smooth Muscle ◽  
And Migration ◽  
Proliferation And Migration

Background/Aims: Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes, and many of which are likely to have functional roles in vascular remodeling. However, their functions in pulmonary arterial hypertension (PAH) remain largely unknown. Pulmonary vascular remodeling is an important pathological feature of PAH, leading to increased vascular resistance and reduced compliance. Pulmonary artery smooth muscle cells (PASMCs) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of PASMCs function. Herein, we determined whether long noncoding RNA–maternally expressed gene 3 (MEG3) was involved in PAH-related vascular remodeling. Methods: The arterial wall thickness was examined by hematoxylin and eosin (H&E) staining in distal pulmonary arteries (PAs) isolated from lungs of healthy volunteers and PAH patients. The expression level of MEG3 was analyzed by qPCR. The effects of MEG3 on human PASMCs were assessed by cell counting Kit-8 assay, BrdU incorporation assay, flow cytometry, scratch-wound assay, immunofluorescence, and western blotting in human PASMCs. Results: We revealed that the expression of MEG3 was significantly downregulated in lung and PAs of patients with PAH. MEG3 knockdown affected PASMCs proliferation and migration in vitro. Moreover, inhibition of MEG3 regulated the cell cycle progression and made more smooth muscle cells from the G0/G1 phase to the G2/M+S phase and the process could stimulate the expression of PCNA, Cyclin A and Cyclin E. In addition, we found that the p53 pathway was involved in MEG3–induced smooth muscle cell proliferation. Conclusions: This study identified MEG3 as a critical regulator in PAH and demonstrated the potential of gene therapy and drug development for treating PAH.

ID: 123: ROLE OF MICRORNA-1 IN REGULATING PULMONARY VASCULAR REMODELING IN PULMONARY ARTERIAL HYPERTENSION

2016 ◽  
Vol 64 (4) ◽  
pp. 969.1-969 ◽  
Author(s):  
JR Sysol ◽  
J Chen ◽  
S Singla ◽  
V Natarajan ◽  
RF Machado ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Luciferase Reporter ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

RationalePulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by increased pulmonary arterial pressure and resistance due in part to uncontrolled vascular remodeling. The mechanisms contributing to vascular remodeling in PAH are poorly understood and involve rampant pulmonary artery smooth muscle cell (PASMC) proliferation. We recently demonstrated the important role of sphingosine kinase 1 (SphK1), a lipid kinase producing pro-proliferative sphingosine-1-phosphate (S1P), in the development of pulmonary vascular remodeling in PAH. However, the regulatory processes involved in upregulation of SphK1 in this disease are unknown.ObjectiveIn this study, we aimed to identify novel molecular mechanisms governing the regulation of SphK1 expression, with a focus on microRNA (miR). Using both in vitro studies in pulmonary artery smooth muscle cells (PASMCs) and an in vivo mouse model of experimental hypoxia-mediated pulmonary hypertension (HPH), we explored the role of miR in controlling SphK1 expression in the development of pulmonary vascular remodeling.Methods and ResultsIn silico analysis identified hsa-miR-1-3p (miR-1) as a candidate targeting SphK1. We demonstrate miR-1 is down-regulated by hypoxia in human PASMCs and in lung tissues of mice with HPH, coinciding with upregulation of SphK1 expression. PASMCs isolated from patients with PAH had significantly reduced expression of miR-1. Transfection of human PASMCs with miR-1 mimics significantly attenuated activity of a SphK1-3'-UTR luciferase reporter construct and SphK1 protein expression. miR-1 overexpression in human PASMCs also inhibited proliferation and migration under normoxic and hypoxic conditions, both important in pathogenic vascular remodeling in PAH. Finally, we demonstrated that intravenous administration of miR-1 mimics prevents the development of experimental HPH in mice and attenuates induction of SphK1 in PASMCs.ConclusionThese data demonstrate that miR-1 expression in reduced in PASMCs from PAH patients, is modulated by hypoxia, and regulates the expression of SphK1. Key phenotypic aspects of vascular remodeling are influenced by miR-1 and its overexpression can prevent the development of HPH in mice. These studies further our understanding of the mechanisms underlying pathogenic pulmonary vascular remodeling in PAH and could lead to novel therapeutic targets.Supported by grants NIH/NHLBI R01 HL127342 and R01 HL111656 to RFM, NIH/NHLBI P01 HL98050 and R01 HL127342 to VN, American Heart Association Predoctoral Fellowship (15PRE2190004) to JRS, and NIH/NLHBI NRSA F30 Fellowship (FHL128034A) to JRS.

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