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  3. Soluble epoxide hydrolase and TRPC3 channels jointly contribute to homocysteine-induced cardiac hypertrophy: Interrelation and regulation by C/EBPβ

Soluble epoxide hydrolase and TRPC3 channels jointly contribute to homocysteine-induced cardiac hypertrophy: Interrelation and regulation by C/EBPβ

  • Biochim Biophys Acta Mol Basis Dis. 2023 Jan 18;1869(4):166643. doi: 10.1016/j.bbadis.2023.166643.
Yang Zhou 1,  Xiang-Chong Wang 2,  Jia-Hui Wei 1,  Hong-Mei Xue 3,  Wen-Tao Sun 4,  Guo-Wei He 5,  Qin Yang 6
Affiliations

Affiliations

  • 1 Center for Basic Medical Research & Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Graduate School of Peking Union Medical College, Tianjin 300457, China.
  • 2 Center for Basic Medical Research & Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Graduate School of Peking Union Medical College, Tianjin 300457, China; Department of Pharmacology, Hebei Higher Education Institute Applied Technology Research Center on TCM Formula Preparation, Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050091, China.
  • 3 Center for Basic Medical Research & Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Graduate School of Peking Union Medical College, Tianjin 300457, China; Department of Physiology, Hebei Medical University, Shijiazhuang 050017, Hebei, China.
  • 4 Center for Basic Medical Research & Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Graduate School of Peking Union Medical College, Tianjin 300457, China; University of Health and Rehabilitation Sciences, Qingdao, Shandong 266000, China.
  • 5 Center for Basic Medical Research & Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Graduate School of Peking Union Medical College, Tianjin 300457, China; Institute of Cardiovascular Diseases, Tianjin University, Tianjin 300457, China; Drug Research and Development Center, Wannan Medical College, Wuhu 241002, Anhui, China; Department of Surgery, Oregon Health and Science University, Portland, OR 97239-3098, USA.
  • 6 Center for Basic Medical Research & Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences & Graduate School of Peking Union Medical College, Tianjin 300457, China; Institute of Cardiovascular Diseases, Tianjin University, Tianjin 300457, China. Electronic address: qyang@tju.edu.cn.
PMID: 36669577 DOI: 10.1016/j.bbadis.2023.166643
Abstract

Objectives: Studies in certain cardiac hypertrophy models suggested the individual role of soluble Epoxide Hydrolase (sEH) and canonical transient receptor potential 3 (TRPC3) channels, however, whether they jointly mediate hypertrophic process remains unexplored. Hyperhomocysteinemia promotes cardiac hypertrophy while the involvement of sEH and TRPC3 channels remains unknown. This study aimed to explore the role of, and interrelation between sEH and TRPC3 channels in homocysteine-induced cardiac hypertrophy.

Methods: Rats were fed methionine-enriched diet to induce hyperhomocysteinemia. H9c2 cells and neonatal rat cardiomyocytes were incubated with homocysteine. Cardiac hypertrophy was evaluated by echocardiography, histological examination, immunofluorescence imaging, and expressions of hypertrophic markers. Epoxyeicosatrienoic acids (EETs) were determined by ELISA. TRPC3 current was recorded by patch-clamp. Gene promotor activity was measured using dual-luciferase reporter assay.

Results: Inhibition of sEH by 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) reduced ventricular mass, lowered the expression of hypertrophic markers, decreased interstitial collagen deposition, and improved cardiac function in hyperhomocysteinemic rats, associated with restoration of EETs levels in myocardium. TPPU or knockdown of sEH suppressed TRPC3 transcription and translation as well as TRPC3 current that were enhanced by homocysteine. Exogenous 11,12-EET inhibited homocysteine-induced TRPC3 expression and cellular hypertrophy. Silencing C/EBPβ attenuated, while overexpressing C/EBPβ promoted homocysteine-induced hypertrophy and expressions of sEH and TRPC3, resulting respectively from inhibition or activation of sEH and TRPC3 gene promoters.

Conclusions: sEH and TRPC3 channels jointly contribute to homocysteine-induced cardiac hypertrophy. Homocysteine transcriptionally activates sEH and TRPC3 genes through a common regulatory element C/EBPβ. sEH activation leads to an upregulation of TRPC3 channels via a 11,12-EET-dependent manner.

Keywords

Cardiac hypertrophy; Homocysteine; Soluble epoxide hydrolase; TRPC3 channels; Transcription factor.

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