Full length articleActivation of PPARγ inhibits HDAC1-mediated pulmonary arterial smooth muscle cell proliferation and its potential mechanisms
Introduction
Pulmonary arterial hypertension (PAH) is a complex and progressive disease characterized by sustained elevation of pulmonary vascular resistance and increased pulmonary arterial pressure, leading to right heart failure and death approximately 5 to 7 years after diagnosis (Benza et al., 2012, Hoeper et al., 2014). The pathological mechanisms underlying the development of PAH include persistent pulmonary vasoconstriction, vascular remodeling, and thrombosis in situ (Miura et al., 2010, Pullamsetti et al., 2016). Pulmonary arterial remodeling, occurring mostly in the distal pulmonary arteries, is extremely critical among these pathogeneses (Vaillancourt et al., 2015). Abnormal pulmonary arterial smooth muscle cell (PASMC) proliferation in situ and migration to intima is critical to the pathogenesis of pulmonary arterial remodeling (Tajsic and Morrell, 2011). Therefore, it is important to explore the molecular mechanisms responsible for PASMC proliferation and search for new targets for the prevention and treatment of PAH.
Histone deacetylases (HDACs) are a family of enzymes that balance the acetylation activities of histone acetyltransferases (HATs) on the post-translational modifications of histone and a wide range of other non-histone proteins (Reichert et al., 2012, Wang et al., 2015). In mammals, HDACs are divided into four groups based on their sequence similarity and function (Wang et al., 2015). Among them, class I HDACs (HDAC1, 2, 3, and 8) play a central role in controlling cell cycle regulation, cell proliferation, and tissue development by deacetylating substrates and then regulating gene expression (Reichert et al., 2012). Studies have shown that selective class I HDAC inhibitor suppresses monocrotaline and hypoxia-induced pulmonary arterial remodeling through an anti-proliferative mechanism (Cavasin et al., 2012, Lan et al., 2015, Zhao et al., 2012). A recent study has found that HDAC1 is a major conductor of platelet-derived growth factor (PDGF)-induced PASMC proliferation in PAH (Galletti et al., 2014). Yet, the molecular mechanisms underlying how HDAC1 mediates PDGF-induced PASMC proliferation are not fully defined.
Peroxisome proliferator-activated receptor γ (PPARγ) is a family member of nuclear receptors that consists of PPARα, PPARβ (also known as PPARδ), and PPARγ. Previous studies have suggested that PPARγ has broad protective effects on the cardiovascular system that surpass the regulation of adipogenesis and glucose metabolism (Gao et al., 2015, Meng et al., 2015). Studies have indicated that activation of PPARγ by pioglitazone, one of the most potent and selective synthetic agonists of PPARγ receptors, suppresses PDGF-induced PASMC proliferation and protects against PAH development in a series of experimental models (Behringer et al., 2016, Dickinson et al., 2014, Osman and Segar, 2016). However, the mechanisms underlying the inhibition of PDGF-induced PASMC proliferation by activation of PPARγ have not been completely understood. To address above issues, cell proliferation and HDAC1 protein level were assessed in primary cultured PASMCs stimulated with PDGF, and the levels of microRNA-124 (miR-124) as well as cyclin-dependent kinase 4 (CDK4) protein were also examined. The effect of PPARγ activation on PASMC proliferation caused by PDGF was tested and the mechanisms were further explored.
Section snippets
Cell preparation and culture
Primary cultured PASMCs were obtained from the main pulmonary arteries of 4- to 5-week-old male Sprague-Dawley rats using the methods described previously (Wu et al., 2014). All animal procedures were approved and conducted adhering to the Laboratory Animal Care Committee of Xi’an Jiaotong University. Briefly, rats were euthanized by CO2 overdose. The pulmonary arteries were rapidly removed and washed in phosphate-buffered saline (PBS) under sterile conditions. Next, a thin layer of the
PDGF stimulates PASMC proliferation
To examine the effect of PDGF on PASMC proliferation, cells were treated with different concentrations of PDGF for different times, and cell proliferation was determined by BrdU incorporation assay. As shown in Fig. 1A, PDGF dose-dependently stimulated PASMC proliferation at 24 h, and 10 ng/ml PDGF triggered a 1.98-fold increase compared with the control group (P < 0.01). Fig. 1B demonstrates that PDGF promoted PASMC proliferation in a time-dependent manner; 10 ng/ml PDGF caused a 2.43-fold
Discussion
In the present study, we have shown that up-regulation of HDAC1 mediates PDGF-induced PASMC proliferation by down-regulation of miR-124 and consequent up-regulation of CDK4 protein. The activation of PPARγ by pioglitazone inhibits PDGF-induced PASMC proliferation, and the mechanisms are associated with PPARγ modulation of HDAC1-mediated miR-124 and CDK4 protein expression (Fig. 9). These results provide important insights into HDAC1 mediation of PASMC proliferation and highlight a novel
Disclosures
The authors declare that they have no competing interests.
Acknowledgment
This work was supported by Chinese National Science Foundation (No. 81670051 and No. 81330002).
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