The Role and Regulation of Pulmonary Artery Smooth Muscle Cells in Pulmonary Hypertension

He, Shixin; Zhu, Tengteng; Fang, Zhenfei

doi:10.1155/2020/1478291

Cited by 13 publications

(11 citation statements)

References 155 publications

(154 reference statements)

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“…Moreover, protein levels of key glycolytic enzymes PFKP and HKII were significantly higher in human PAH PAVSMC compared to controls ( Figures 2E–G ), and HIF1α over accumulation was detected in six out of seven PAVSMC from PAH patients compared to one out of five non-diseased (control) subjects ( Supplementary Figure 2 ). This is in good agreement with previously published data demonstrating the importance of glycolysis for PH ( 19 , 36 , 37 ). Together, our data demonstrate that glycolysis-metabolized glucose serves as a main source for increased de novo lipid synthesis in PAH PAVSMC, supporting a pro-proliferative cell phenotype.…”

Section: Resultssupporting

confidence: 93%

Akt-Dependent Glycolysis-Driven Lipogenesis Supports Proliferation and Survival of Human Pulmonary Arterial Smooth Muscle Cells in Pulmonary Hypertension

Jiang

Goncharov²,

Shen³

et al. 2022

Front. Med.

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Hyper-proliferation of pulmonary arterial vascular smooth muscle cells (PAVSMC) is an important pathological component of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Lipogenesis is linked to numerous proliferative diseases, but its role in PAVSMC proliferation in PAH remains to be elucidated. We found that early-passage human PAH PAVSMC had significant up-regulation of key fatty acids synthesis enzymes ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FASN), and increased unstimulated proliferation compared to control human PAVSMC. Treatment with an allosteric ACC inhibitor 5-tetradecyloxy-2-furoic acid (TOFA) significantly decreased proliferation and induced apoptosis of human PAH PAVSMC. Intracellular lipid content and proliferation of PAH PAVSMC were not reduced by incubation in lipid-depleted media but suppressed by a non-metabolizable analog of glucose 2-Deoxy-D-glucose (2-DG) and partially restored by addition of pyruvate. Protein kinase Akt was upregulated in human PAH PAVSMC in a sirtuin 7 (SIRT7)- and c-Jun N-terminal kinase (JNK)-dependent manner. Pharmacological inhibition of Akt down-regulated ACLY and ACC, significantly reduced intracellular lipid content, inhibited proliferation and induced apoptosis of human PAH PAVSMC. Taken together, these data demonstrate that human PAH PAVSMC have up-regulated lipogenesis, which is supported in an Akt- and glycolysis-dependent manner and is required for increased proliferation and survival. Our data suggest that there is a mechanistic link between glycolysis, lipogenesis, and the proliferation of human PAH PAVSMC and call for further studies to determine the potential attractiveness of a SIRT7/JNK-Akt-lipogenesis axis as a target pathway to inhibit PAVSMC hyper-proliferation in PAH.

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Section: Resultssupporting

confidence: 93%

Akt-Dependent Glycolysis-Driven Lipogenesis Supports Proliferation and Survival of Human Pulmonary Arterial Smooth Muscle Cells in Pulmonary Hypertension

Jiang

Goncharov²,

Shen³

et al. 2022

Front. Med.

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“…Pulmonary artery vasoconstriction and remodeling are factors responsible for the increased vascular resistance seen in patients with PH [ 28 ]. The abnormal balance in vascular smooth muscle cell (VSMC) hypertrophy, excessive proliferation and apoptosis results in the formation of the characteristic angio-proliferative lesions found in PH [ 29 ]. PH can induce the increased expression and activity of ROCK in the lung vasculature of patients and in rodent models of primary or secondary PH [ 29 , 30 ].…”

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

“…The abnormal balance in vascular smooth muscle cell (VSMC) hypertrophy, excessive proliferation and apoptosis results in the formation of the characteristic angio-proliferative lesions found in PH [ 29 ]. PH can induce the increased expression and activity of ROCK in the lung vasculature of patients and in rodent models of primary or secondary PH [ 29 , 30 ]. The activation of ROCK plays an important role in regulating the VSMC structure and function and mediating signaling pathways involved in their migration, proliferation and apoptosis.…”

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Montagnoli

Sudo

et al. 2021

Cells

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Pulmonary hypertension (PH) is a cardiovascular disease caused by extensive vascular remodeling in the lungs, which ultimately leads to death in consequence of right ventricle (RV) failure. While current drugs for PH therapy address the sustained vasoconstriction, no agent effectively targets vascular cell proliferation and tissue inflammation. Rho-associated protein kinases (ROCKs) emerged in the last few decades as promising targets for PH therapy, since ROCK inhibitors demonstrated significant anti-remodeling and anti-inflammatory effects. In this review, current aspects of ROCK inhibition therapy are discussed in relation to the treatment of PH and RV dysfunction, from cell biology to preclinical and clinical studies.

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“…Biomedical advances over the last decade have identified the central role of proliferative pulmonary arterial smooth muscle cells (PASMCs) in the development of PAH (He et al, 2020;Hu et al, 2015). There is a tendency to think that excessive proliferation and resistance to apoptosis of PASMCs is the crucial component of pulmonary vascular remodeling (He et al, 2020). Different triggers have been described to lead to uncontrolled PASMCs, such as inflammation, hypoxia and shear stress or vascular injury.…”

Section: Introductionmentioning

confidence: 99%

Ganoderic Acid A suppresses the phenotypic modulation of pulmonary artery smooth muscle cells through the inactivation of PI3K/Akt pathway in pulmonary arterial hypertension

Meng¹,

Ning²,

Liu³

et al. 2022

Food Sci. Technol

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Ganoderic acid A (GAA) is one of the most abundant triterpenoids in Ganoderma lucidum and has protective effect on several vascular diseases. However, the effect of GAA on pulmonary arterial hypertension (PAH) has not been reported. The aim of this study was to investigate the effect of the GAA on the hypoxia-induced phenotypic modulation of PASMCs and the involved transduction pathway. Primary rat pulmonary artery smooth muscle cells (PASMCs) were isolated and cultured under hypoxia condition to induce phenotypic modulation. Our results showed that hypoxia significantly increased the proliferation and migration of PASMCs, as well as inhibited the apoptosis of PASMCs, which were blocked by GAA treatment. In addition, hypoxia-induced dedifferentiation of PASMCs was prevented by GAA with increased the expression levels of myocardin and calponin, and decreased the expression of osteopontin (OPN). Furthermore, GAA suppressed the hypoxia-induced expression of p-PI3K and p-Akt in PASMCs. Treatment with IGF-1 reversed the effects of GAA on proliferation, migration, apoptosis and dedifferentiation in hypoxia-treated PASMCs. Taken together, these findings demonstrated that GAA suppresses the phenotypic modulation of PASMCs through the inactivation of PI3K/Akt pathway. Thus, GAA may be a potent therapeutic agent for PAH in future clinical practice.

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The Role and Regulation of Pulmonary Artery Smooth Muscle Cells in Pulmonary Hypertension

Cited by 13 publications

References 155 publications

Akt-Dependent Glycolysis-Driven Lipogenesis Supports Proliferation and Survival of Human Pulmonary Arterial Smooth Muscle Cells in Pulmonary Hypertension

Akt-Dependent Glycolysis-Driven Lipogenesis Supports Proliferation and Survival of Human Pulmonary Arterial Smooth Muscle Cells in Pulmonary Hypertension

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Ganoderic Acid A suppresses the phenotypic modulation of pulmonary artery smooth muscle cells through the inactivation of PI3K/Akt pathway in pulmonary arterial hypertension

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