Soluble epoxide hydrolase inhibitor, TUPS, attenuates isoproterenol/angiotensin II-induced cardiac hypertrophy through mammalian target of rapamycin-mediated autophagy inhibition

Abstract

Objectives To investigate the potential role and mechanism of TUPS, a soluble epoxide hydrolase inhibitor, in cardiac hypertrophy. Methods Rat and H9C2 cell models of cardiac hypertrophy were induced by isoproterenol and angiotensin II, respectively, followed by TUPS treatment. The expression of hypertrophic markers, ANP and BNP, was determined by quantitative real‐time PCR. The abundance of Beclin‐1, LC3, p‐AMPK and phosphorylated‐mammalian target of rapamycin (p‐mTOR) proteins was analysed by Western blot and immunohistocytology. Cell morphology and viability were evaluated by F‐actin staining and MTS. H9C2 cells were transfected with GFP‐LC3 to evaluate autophagy flux. Key findings TUPS significantly inhibited rat heart size, heart weight‐to‐body weight ratio, heart wall thickness, hypertrophic H9C2 cell swelling and viability suppression as well as the expression of ANP and BNP genes in hypertrophic models. In addition, autophagic markers Beclin‐1 and LC3 were elevated in both cellular and animal models, which were suppressed by TUPS, with corresponding changes of autophagy flux. The abundance of p‐AMPK was increased, while p‐mTOR was decreased in hypertrophic cells, which were abolished by TUPS. Rapamycin decreased p‐mTOR level, increased Beclin‐1 and LC3 expression and induced cell size enlargement and cell viability inhibition in hypertrophic H9C2 cells treated with TUPS. Conclusions TUPS inhibits cardiac hypertrophy by regulating mTOR/autophagy axis.

Ginkgolide B Protects Cardiomyocytes from Angiotensin II-Induced Hypertrophy via Regulation of Autophagy through SIRT1-FoxO1

“…However, there are conflicting reports on the role of autophagy in Ang II-induced cardiac hypertrophy [ 19 ]. Some studies showed that inhibition of the Ang II-induced autophagy suppressed cardiac hypertrophy [ 20 , 21 ]. In contrast, others showed that activation of Ang II-induced autophagy suppressed cardiac hypertrophy [ 22 , 23 ].…”

Discovery of Soluble Epoxide Hydrolase Inhibitors from Chemical Synthesis and Natural Products

“…201,202 For example, TUPS treatment reduced the thickness of the heart wall, downregulated the expression of hypertrophy markers atrial and brain natriuretic peptides, and regulated negative autophagy via activation of mammalian target of rapamycin (mTOR) signaling, allowing prevention of myocardial hypertrophy induced by isoproterenol. 202 These data all suggested the therapeutic potential of sEH in heart failure.…”

“…Moreover, increasing EET levels protected against myocardial infarction and left ventricular dysfunction after ischemic injury in Ephx2 –/– mice . Inhibition of sEH with GSK2188931B and TUPS both protected heart failure. , For example, TUPS treatment reduced the thickness of the heart wall, downregulated the expression of hypertrophy markers atrial and brain natriuretic peptides, and regulated negative autophagy via activation of mammalian target of rapamycin (mTOR) signaling, allowing prevention of myocardial hypertrophy induced by isoproterenol . These data all suggested the therapeutic potential of sEH in heart failure.…”

Inhibition of soluble epoxide hydrolase attenuates renal tubular mitochondrial dysfunction and ER stress by restoring autophagic flux in diabetic nephropathy

“…Numerous studies have highlighted the potential benefits of sEH inhibition in the inflammatory response 20 , cardiovascular diseases 21 , non-alcoholic fatty liver 22 and renal disease [23][24][25] . A recent study demonstrated that the sEH inhibitor TUPS mitigated isoproterenol/angiotensin IIinduced cardiac hypertrophy by inhibiting mTOR signaling-mediated autophagy 26 , which indicated that sEH is associated with the regulation of autophagy. Furthermore, previous evidence demonstrated that the stabilization of EpFA by treatment with an sEH inhibitor prevented mitochondrial dysfunction, which subsequently reduced ROS generation and blocked the activation of ER stress in diverse diseases including diabetes, cardiovascular and neurodegenerative diseases 27 .…”