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CPT1 regulates the proliferation of pulmonary artery smooth muscle cells through the AMPK-p53-p21 pathway in pulmonary arterial hypertension

  • Wei Zhuang
  • Guili Lian
  • Bangbang Huang
  • Apang Du
  • Jin Gong
  • Genfa Xiao
  • Changsheng Xu
  • Huajun Wang
  • Liangdi Xie
Article

Abstract

Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) plays a dominant role in the development of pulmonary arterial hypertension (PAH). Some studies and our previous work found that disturbance of fatty acid metabolism existed in PAH. However, the mechanistic link between fatty acid catabolism and cell proliferation remains elusive. Here, we identified an essential role and signal pathway for the key rate-limiting enzyme of mitochondrial fatty acid β-oxidation, carnitine palmitoyltransferase (CPT) 1, in regulating PASMC proliferation in PAH. We found that CPT1 was highly expressed in rat lungs and pulmonary arteries in monocrotaline-induced PAH, accompanied by decreased adenosine triphosphate (ATP) production and downregulation of the AMPK-p53-p21 pathway. Platelet-derived growth factor (PDGF)-BB upregulated the expression of CPT1 in a dose- and time-dependent manner. PASMC proliferation and ATP production induced by PDGF-BB were partly reversed by the CPT1 inhibitor etomoxir (ETO). The overexpression of CPT1 in PASMCs also promoted proliferation and ATP production and subsequently inhibited the phosphorylation of AMPK, p53, as well as p21 in PASMCs. Furthermore, AMPK was activated by ETO, which increased the expression of p53 and p21, and the proportion of cells in the cell cycle G2/M phase in response to PDGF-BB stimulation in PASMCs. Our work reveals a novel mechanism of CPT1 regulating PASMC proliferation in PAH, and regulation of CPT1 may be a potential target for therapeutic intervention in PAH.

Keywords

Pulmonary arterial hypertension Pulmonary artery smooth muscle cell Carnitine palmitoyltransferase 1 AMP-activated protein kinase p21 

Abbreviations

PASMCs

Pulmonary artery smooth muscle cells

PAH

Pulmonary arterial hypertension

CPT

Carnitine palmitoyltransferase

ATP

Adenosine triphosphate

PDGF

Platelet-derived growth factor

ETO

Etomoxir

FAO

Fatty acid β-oxidation

CPT1

Carnitine palmitoyltransferase 1

MCT

Monocrotaline

AMPK

Activated protein kinase

RVHI

Right ventricular hypertrophy index

ATP

Adenosine triphosphate

MTT

Methyl thiazolyl tetrazolium bromide

mPAP

Mean pulmonary arterial pressure

Notes

Acknowledgements

This work was supported by project grants from the National Natural Science Foundation of China (Nos. 81570446 and 81700267) and Fujian Provincial Department of Science and Technology (2017J01288 and 2016J05179). The authors express their gratitude to Zhen Huang for taking images with a confocal microscope, Lengxi Fu and Junying Chen for their help in the flow cytometric analysis, and Li Liu for her secretarial assistance in the preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of CardiologyThe First Affiliated Hospital of Fujian Medical UniversityFuzhouPeople’s Republic of China
  2. 2.Fujian Hypertension Research InstituteThe First Affiliated Hospital of Fujian Medical UniversityFuzhouPeople’s Republic of China
  3. 3.Department of GeriatricThe First Affiliated Hospital of Fujian Medical UniversityFuzhouPeople’s Republic of China

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