(843.4) Soluble Epoxide Hydrolase Inhibitor Prevents Homocysteine-induced Cardiac Hypertrophy via Epoxyeicosatrienoic Acid–mediated Inhibition of TRPC3 Channels

Poster Board Number: B159

Yang Zhou (Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College, Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College), Xiang-Chong Wang (Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College, Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College), Wen-Tao Sun (Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College, Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College), Hong-Mei Xue (Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College, Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College, Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College), Guo-Wei He (Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College, Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College, Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College, Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College), Qin Yang (Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College, Center for Basic Medical Research amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences amp; Peking Union Medical College)

Objectives:  Activation of soluble epoxide hydrolase (sEH), a key enzyme catalyzing the degradation of epoxyeicosatrienoic acids (EETs), has been implicated in cardiac remodeling. We previously demonstrated the involvement of sEH and transient receptor potential isoform 3 (TRPC3) channels in homocysteine-induced hypertrophy of cardiac cells. This study investigated the anti-hypertrophic effect of sEH inhibitor with the aim to reveal the link between sEH/EETs and TRPC3 channels in cardiac hypertrophy associated with hyperhomocysteinemia.   

Materials and methods: Male Wistar rats on 10-week standard or 2% (WT/WT) high methionine diet were given drinking water supplemented with or without the specific sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU, 5mg/L). In vitro, H9c2 cells were treated with homocysteine (100 μmol/L) in the presence or absence of TPPU (10 μmol/L) or 11,12-EET (1 μmol/L). Cardiac remodeling was evaluated by echocardiography and histological analysis. Plasma homocysteine level and EETs content were determined by ELISA. Hypertrophic markers were detected by western blot and qPCR. TRPC3 channel current was recorded by patch clamp in whole-cell mode.

Results:  TPPU lowered the heart to body weight ratio, inhibited expressions of the hypertrophic markers atrial natriuretic factor (ANP) and β-myosin heavy chain (β-MHC), and reduced the size of cardiomyocytes in hyperhomocysteinemic rats. TPPU treatment ameliorated ejection fraction (85.50±0.87% vs. 74.18±2.19%, plt;0.05) and fraction shortening (50.30±1.32% vs. 42.27±0.68%, plt;0.01) of the hyperhomocysteinemic rats. Rats with hyperhomocysteinemia showed reduced levels of EETs and increased expression of TRPC3 channels, which were reversed by TPPU treatment. In vitro, TPPU and 11,12-EET inhibited H9c2 cell enlargement induced by homocysteine, along with a downregulation of hypertrophic markers and TRPC3 channels. Homocysteine significantly increased TRPC3 channel current (4.74±0.49 vs. 1.76±0.21 pA/pF in control, plt;0.001) and the enhancement was inhibited by TPPU (2.44±0.29 pA/pF, plt;0.01).

Conclusions:  Inactivation of sEH alleviates homocysteine-induced cardiac hypertrophy and improves cardiac function. EET-mediated inhibition of TRPC3 channels contributes to the protective effect of the sEH inhibitor TPPU.

lt;igt;Supported by NSFC 81870227 amp;amp; 81870288 amp;amp; 82170353, lt;/igt;lt;igt;Tianjin Science and Technology Commission 20JCZDJC00510lt;/igt;lt;igt; amp;amp; lt;/igt;lt;igt;18PTZWHZ00060lt;/igt;lt;igt;, and Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences 2020-PT310-007.lt;/igt;