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

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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.

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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

References

  1. Tuder RM, Archer SL, Dorfmuller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR, Morrell NW (2013) Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 62:D4–D12

    Article  PubMed  PubMed Central  Google Scholar 

  2. Li MX, Jiang DQ, Wang Y, Chen QZ, Ma YJ, Yu SS, Wang Y (2016) Signal mechanisms of vascular remodeling in the development of pulmonary arterial hypertension. J Cardiovasc Pharmacol 67:182–190

    Article  CAS  PubMed  Google Scholar 

  3. Xie L, Lin P, Xie H, Xu C (2010) Effects of atorvastatin and losartan on monocrotaline-induced pulmonary artery remodeling in rats. Clin Exp Hypertens 32:547–554

    Article  CAS  PubMed  Google Scholar 

  4. Liang M, Li H, Zheng S, Ning J, Xu C, Wang H, Xie L (2015) Comparison of early and delayed transplantation of adipose tissue-derived mesenchymal stem cells on pulmonary arterial function in monocrotaline-induced pulmonary arterial hypertensive rats. Eur Heart J Suppl 17:F4–F12

    Article  Google Scholar 

  5. Zhao Y, Peng J, Lu C, Hsin M, Mura M, Wu L, Chu L, Zamel R, Machuca T, Waddell T, Liu M, Keshavjee S, Granton J, de Perrot M (2014) Metabolomic heterogeneity of pulmonary arterial hypertension. PLoS ONE 9:e88727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lin T, Gu J, Huang C, Zheng S, Lin X, Xie L, Lin D (2016) (1)H NMR-based analysis of serum metabolites in monocrotaline-induced pulmonary arterial hypertensive rats. Dis Mark 2016:5803031

    Google Scholar 

  7. Wong BW, Wang X, Zecchin A, Thienpont B, Cornelissen I, Kalucka J, Garcia-Caballero M, Missiaen R, Huang H, Bruning U et al (2017) The role of fatty acid beta-oxidation in lymphangiogenesis. Nature 542:49–54

    Article  CAS  PubMed  Google Scholar 

  8. Liu Y, Zuckier LS, Ghesani NV (2010) Dominant uptake of fatty acid over glucose by prostate cells: a potential new diagnostic and therapeutic approach. Anticancer Res 30:369–374

    PubMed  Google Scholar 

  9. Sutendra G, Bonnet S, Rochefort G, Haromy A, Folmes KD, Lopaschuk GD, Dyck JR, Michelakis ED (2010) Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. Sci Transl Med 2:44ra58

    Article  CAS  PubMed  Google Scholar 

  10. Pucci S, Zonetti MJ, Fisco T, Polidoro C, Bocchinfuso G, Palleschi A, Novelli G, Spagnoli LG, Mazzarelli P (2016) Carnitine palmitoyl transferase-1A (CPT1A): a new tumor specific target in human breast cancer. Oncotarget 7:19982–19996

    Article  PubMed  PubMed Central  Google Scholar 

  11. Abo Alrob O, Lopaschuk GD (2014) Role of CoA and acetyl-CoA in regulating cardiac fatty acid and glucose oxidation. Biochem Soc Trans 42:1043–1051

    Article  CAS  PubMed  Google Scholar 

  12. Teng H, Sui X, Zhou C, Shen C, Yang Y, Zhang P, Guo X, Huo R (2016) Fatty acid degradation plays an essential role in proliferation of mouse female primordial germ cells via the p53-dependent cell cycle regulation. Cell Cycle 15:425–431

    Article  CAS  PubMed  Google Scholar 

  13. Zhuang W, Lian G, Huang B, Du A, Xiao G, Gong J, Xu C, Wang H, Xie L (2018) Pulmonary arterial hypertension induced by a novel method: twice-intraperitoneal injection of monocrotaline. Exp Biol Med 12:1535370218794128. https://doi.org/10.1177/1535370218794128

    Article  CAS  Google Scholar 

  14. Luo L, Zheng W, Lian G, Chen H, Li L, Xu C, Xie L (2018) Combination treatment of adipose-derived stem cells and adiponectin attenuates pulmonary arterial hypertension in rats by inhibiting pulmonary arterial smooth muscle cell proliferation and regulating the AMPK/BMP/Smad pathway. Int J Mol Med 41:51–60

    CAS  PubMed  Google Scholar 

  15. Huang J, Xie LD, Luo L, Zheng SL, Wang HJ, Xu CS (2014) Silencing heat shock protein 27 (HSP27) inhibits the proliferation and migration of vascular smooth muscle cells in vitro. Mol Cell Biochem 390:115–121

    Article  CAS  PubMed  Google Scholar 

  16. Chen HF, Xie LD, Xu CS (2010) The signal transduction pathways of heat shock protein 27 phosphorylation in vascular smooth muscle cells. Mol Cell Biochem 333:49–56

    Article  CAS  PubMed  Google Scholar 

  17. Perros F, Montani D, Dorfmuller P, Durand-Gasselin I, Tcherakian C, Le Pavec J, Mazmanian M, Fadel E, Mussot S, Mercier O, Herve P, Emilie D, Eddahibi S, Simonneau G, Souza R, Humbert M (2008) Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 178(1):81–88

    Article  CAS  PubMed  Google Scholar 

  18. Ouyang QF, Han Y, Lin ZH, Xie H, Xu CS, Xie LD (2014) Fluvastatin upregulates the α1c subunit of CaV1.2 channel expression in vascular smooth muscle cells via RhoA and ERK/p38 MAPK pathways. Dis Mark. https://doi.org/10.1155/2014/237067

    Article  Google Scholar 

  19. Zhong H, Wang T, Lian G, Xu C, Wang H, Xie L (2018) TRPM7 regulates angiotensin II-induced sinoatrial node fibrosis in sick sinus syndrome rats by mediating Smad signaling. Heart Vessels 33:1094–1105

    Article  PubMed  PubMed Central  Google Scholar 

  20. Linher-Melville K, Zantinge S, Sanli T, Gerstein H, Tsakiridis T, Singh G (2010) Establishing a relationship between prolactin and altered fatty acid [beta]-oxidation via carnitine palmitoyl transferase 1 in breast cancer cells. BMC Cancer 11:56

    Article  CAS  Google Scholar 

  21. Price LC, Wort SJ, Perros F, Dorfmüller P, Huertas A, Montani D, Cohenkaminsky S, Humbert M (2012) Inflammation in pulmonary arterial hypertension. Chest 141:210–221

    Article  CAS  PubMed  Google Scholar 

  22. Voelkel NF, Tamosiuniene R, Nicolls MR (2016) Challenges and opportunities in treating inflammation associated with pulmonary hypertension. Expert Rev Cardiovasc Ther 14:939–951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Meloche J, Renard S, Provencher S, Bonnet S (2013) Anti-inflammatory and immunosuppressive agents in PAH. Handb Exp Pharmacol 218:437–476

    Article  CAS  PubMed  Google Scholar 

  24. Song Y, Wu Y, Su X, Zhu Y, Liu L, Pan Y, Zhu B, Yang L, Gao L, Li M (2016) Activation of AMPK inhibits PDGF-induced pulmonary arterial smooth muscle cells proliferation and its potential mechanisms. Pharmacol Res 107:117–124

    Article  CAS  PubMed  Google Scholar 

  25. Cui C, Zhang H, Guo LN, Zhang X, Meng L, Pan X, Wei Y (2016) Inhibitory effect of NBL1 on PDGF-BB-induced human PASMC proliferation through blockade of PDGFβ-p38MAPK pathway. Biosci Rep 36:e00374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Assad TR, Hemnes AR (2015) Metabolic dysfunction in pulmonary arterial hypertension. Curr Hypertens Rep 17:20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rafikov R, Sun X, Rafikova O, Meadows ML, Desai AA, Khalpey Z, Yuan XJ, Fineman JR, Black SM (2015) Complex I dysfunction underlies the glycolytic switch in pulmonary hypertensive smooth muscle cells. Redox Biol 6:278–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nguyen QL, Corey C, White P, Watson A, Gladwin MT, Simon MA, Shiva S (2017) Platelets from pulmonary hypertension patients show increased mitochondrial reserve capacity. JCI Insight 2:e91415

    Article  PubMed  PubMed Central  Google Scholar 

  29. Jiang Z, Knudsen NH, Wang G, Qiu W, Naing ZZ, Bai Y, Ai X, Lee CH, Zhou X (2017) Genetic control of fatty scid β-oxidation in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 56:738–748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xiao Y, Peng H, Hong C, Chen Z, Deng X, Wang A, Yang F, Yang L, Chen C, Qin X (2017) PDGF promotes the Warburg effect in pulmonary arterial smooth musclecells via activation of the PI3K/AKT/mTOR/HIF-1alpha signaling pathway. Cell Physiol Biochem 42:1603–1613

    Article  CAS  PubMed  Google Scholar 

  31. Nakamura MT, Yudell BE, Loor JJ (2014) Regulation of energy metabolism by long-chain fatty acids. Prog Lipid Res 53:124–144

    Article  CAS  PubMed  Google Scholar 

  32. Han van der Kolk JH, Gross JJ, Gerber V, Bruckmaier RM (2017) Disturbed bovine mitochondrial lipid metabolism: a review. Vet Q 37:262–273

    Article  Google Scholar 

  33. Xu XD, Shao SX, Jiang HP, Cao YW, Wang YH, Yang XC, Wang YL, Wang XS, Niu HT (2015) Warburg effect or reverse Warburg effect? a review of cancer metabolism. Oncol Res Treat 38:117–122

    Article  CAS  PubMed  Google Scholar 

  34. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Stark R, Reichenbach A, Andrews ZB (2015) Hypothalamic carnitine metabolism integrates nutrient and hormonal feedback to regulate energy homeostasis. Mol Cell Endocrinol 418 Pt 1:9–16

    Article  CAS  Google Scholar 

  36. Liu N, Parry S, Xiao Y, Zhou S, Liu Q (2017) Molecular targets of the Warburg effect and inflammatory cytokines in the pathogenesis of pulmonary artery hypertension. Clin Chim Acta 466:98–104

    Article  CAS  PubMed  Google Scholar 

  37. Cottrill KA, Chan SY (2013) Metabolic dysfunction in pulmonary hypertension: the expanding relevance of the Warburg effect. Eur J Clin Investig 43:855–865

    Article  CAS  Google Scholar 

  38. Zimmermann H (2016) Extracellular ATP and other nucleotides-ubiquitous triggers of intercellular messenger release. Purinergic Signal 12:25–57

    Article  CAS  PubMed  Google Scholar 

  39. Xiao G-F, Xu S-H, Chao Y, Xie L-D, Xu C-S, Wang H-J (2014) PPARδ activation inhibits homocysteine-induced p22(phox) expression in EA.hy926 cells through reactive oxygen species/p38MAPK pathway. Eur J Pharmacol 727:29–34

    Article  CAS  PubMed  Google Scholar 

  40. Ouyang QF, Han Y, Lin ZH, Xie H, Xu CS, Xie LD (2014) Fluvastatin upregulates the α1C subunit of CaV1.2 channel expression in vascular smooth muscle cells via RhoA and ERK/p38 MAPK pathways. Dis Mark 2014:237067

    Google Scholar 

  41. Agarwal S, Bell CM, Rothbart SB, Moran RG (2015) AMP-activated protein kinase (AMPK) control of mTORC1 is p53- and TSC2-independent in pemetrexed-treated carcinoma cells. J Biol Chem 290:27473–27486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. RG J, DR P, CB SKMBJMYXMJB T (2005) AMP-activated protein pinase induces a p53-dependent metabolic checkpoint. Mol Cell 18:283–293

    Article  CAS  Google Scholar 

  43. Jacquin S, Rincheval V, Mignotte B, Richard S, Humbert M, Mercier O, Londoã±O-Vallejo A, Fadel E, Eddahibi S (2015) Inactivation of p53 is sufficient to induce development of pulmonary hypertension in rats. PLoS ONE 10:e0131940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tuder RM, Archer SL, Dorfmüller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR, Morrell NW (2013) Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 62:D4–D12

    Article  PubMed  PubMed Central  Google Scholar 

  45. Rath SL, Senapati S (2016) Mechanism of p27 unfolding for CDK2 reactivation. Sci Rep 6:26450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xie LD, Ke-Gui WU, Chen DG, Dhughes A, Clunn Z, Lymn J (1998) Mechanism involved in the migration of vascular smooth muscle cells inducedby platelet-derived growth factor. Chin J Arterioscler 6:10–14

    Google Scholar 

  47. Xie LD, Clunn GF, Lymn JS, Hughes AD (1998) Role of intracellular calcium ([Ca2+]i) and tyrosine phosphorylation in adhesion of cultured vascular smooth muscle cells to fibrinogen. Cardio Res 39:475–484

    Article  CAS  Google Scholar 

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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.

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  1. Wei Zhuang and Guili Lian contribute equally to this work.

Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China

    Wei Zhuang

  2. Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, People’s Republic of China

    Guili Lian, Apang Du, Jin Gong, Genfa Xiao, Changsheng Xu, Huajun Wang & Liangdi Xie

  3. Department of Geriatric, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China

    Bangbang Huang & Liangdi Xie

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  1. Wei Zhuang
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Zhuang, W., Lian, G., Huang, B. et al. CPT1 regulates the proliferation of pulmonary artery smooth muscle cells through the AMPK-p53-p21 pathway in pulmonary arterial hypertension. Mol Cell Biochem 455, 169–183 (2019). https://doi.org/10.1007/s11010-018-3480-z

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