Background: Hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs) and consequent pulmonary vascular remodeling are the crucial pathological features of pulmonary hypertension (PH). Protein methylation has been shown to be critically involved in PASMC proliferation and PH, but the underlying mechanism remains largely unknown.
Methods: PH animal models were generated by treating mice/rats with chronic hypoxia for 4 weeks. SMYD2-vTg mice (vascular smooth muscle cell-specific suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 (deformed epidural auto-regulatory factor-1) domain-containing protein 2 transgenic) or wild-type rats and mice treated with LLY-507 (3-cyano-5-{2-[4-[2-(3-methylindol-1-yl)ethyl]piperazin-1-yl]-phenyl}-N-[(3-pyrrolidin-1-yl)propyl]benzamide) were used to investigate the function of SMYD2 (suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 domain-containing protein 2) on PH development in vivo. Primary cultured rat PASMCs with SMYD2 knockdown or overexpression were used to explore the effects of SMYD2 on proliferation and to decipher the underlying mechanism.
Results: We demonstrated that the expression of the lysine methyltransferase SMYD2 was upregulated in the smooth muscle cells of pulmonary arteries from patients with PH and hypoxia-exposed rats/mice and in the cytoplasm of hypoxia-induced rat PASMCs. More importantly, targeted inhibition of SMYD2 by LLY-507 significantly attenuated hypoxia-induced pulmonary vascular remodeling and PH development in both male and female rats in vivo and reduced rat PASMC hyperproliferation in vitro. In contrast, SMYD2-vTg mice exhibited more severe PH phenotypes and related pathological changes than nontransgenic mice after 4 weeks of chronic hypoxia treatment. Furthermore, SMYD2 overexpression promoted, while SMYD2 knockdown suppressed, the proliferation of rat PASMCs by affecting the cell cycle checkpoint between S and G2 phases. Mechanistically, we revealed that SMYD2 directly interacted with and monomethylated PPARγ (peroxisome proliferator-activated receptor gamma) to inhibit the nuclear translocation and transcriptional activity of PPARγ, which further promoted mitophagy to facilitate PASMC proliferation and PH development. Furthermore, rosiglitazone, a PPARγ agonist, largely abolished the detrimental effects of SMYD2 overexpression on PASMC proliferation and PH.
Conclusions: Our results demonstrated that SMYD2 monomethylates nonhistone PPARγ and inhibits its nuclear translocation and activation to accelerate PASMC proliferation and PH by triggering mitophagy, indicating that targeting SMYD2 or activating PPARγ are potential strategies for the prevention of PH.
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http://dx.doi.org/10.1161/CIRCRESAHA.124.323698 | DOI Listing |
Toxicol Appl Pharmacol
December 2024
Department of Respiratory Medicine, China-Japan Union Hospital of Jilin University, Changchun 130000, China. Electronic address:
Abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) leading to pulmonary vascular remodeling are critical factors in the development of pulmonary hypertension (pH). Dehydrodiisoeugenol (DEH), a natural phenolic compound, is renowned for its antioxidant and anti-inflammatory properties. However, the precise role and mechanisms of DEH in PH remain unclear.
View Article and Find Full Text PDFJ Biochem Mol Toxicol
January 2025
Environmental Exposures Vascular Disease Institute, Shanxi Medical University, Taiyuan, Shanxi, China.
Pulmonary hypertension is a progressive disease associated with remodeling of the pulmonary vasculature. Excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) play important roles in nicotine-induced vascular injury. Connexin 43 (Cx43) is involved in intracellular communication and regulation of the pulmonary vasculature.
View Article and Find Full Text PDFZhongguo Zhong Yao Za Zhi
October 2024
Qinghai University Xining 810001, China Research Center for High Altitude Medicine, Medical College, Qinghai University Xining 810001, China.
This study aims to investigate the effect of Zhishi Xiebai Guizhi Decoction on the phenotypic transformation of pulmonary artery smooth muscle cells(PASMCs) in rats with hypoxic pulmonary hypertension(HPH). Healthy SPF SD rats were randomly assigned to five groups: control group, hypoxia model group, hypoxia + low-dose Zhishi Xiebai Guizhi Decoction group(440 mg·kg~(-1)·d~(-1)), hypoxia + high-dose Zhishi Xiebai Guizhi Decoction group(880 mg·kg~(-1)·d~(-1)), and hypoxia + sildenafil group(30 mg·kg~(-1)·d~(-1)), with right rats in each group. Rats in the hypoxia model and hypoxia + drug groups were exposed to a hypobaric oxygen chamber with a simulated altitude of 5 000 m to induce the PH model.
View Article and Find Full Text PDFElevated circulating hepcidin levels have been reported in patients with pulmonary artery hypertension (PAH). Hepcidin has been shown to promote proliferation of human pulmonary artery smooth muscle cells (PASMCs) in vitro, suggesting a potential role in PAH pathogenesis. However, the role of human pulmonary artery endothelial cells (PAECs) as either a source of hepcidin, or the effect of hepcidin on PAEC function is not as well described.
View Article and Find Full Text PDFRespir Res
December 2024
Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Background: Pulmonary hypertension (PH) is a malignant vascular disease characterized by pulmonary arterial remodeling. Neural cell adhesion molecule 1 (NCAM1) is a cell surface glycoprotein that is involved in a variety of diseases, including cardiovascular disease. However, the role of NCAM1 in PH remains underexplored.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!