Epoxyeicosatrienoic acid prevents maladaptive remodeling in pressure overload by targeting calcineurin/NFAT and Smad-7.

Abstract

BACKGROUND:

Emerging evidence demonstrates that epoxyeicosatrienoic acids (EETs) as important active eicosanoids that regulate cardiovascular homeostasis, but the mechanisms underlying its favorable anti-hypertrophic benefits in overpressure model remain obscure.

METHODS AND RESULTS:

Four weeks after transverse aortic constriction (TAC), TAC mice developed maladaptive cardiac hypertrophy and consequent cardiac failure. Conversely, a cardiotropic adeno-associated viral vector (AAV9) encoding CYP2J2 prevented transverse aortic constriction-induced cardiac hypertrophy with preserved ejection fraction. EET also conferred protection against phenylephrine-induced hypertrophy in H9c2 cardiomyoblasts. Further investigations indicate CYP2J2/EET exerts protection against cardiac hypertrophy through opposing the increase of intracellular Ca2+ level and Ca2+-mediated calcineurin/NFATc3 signaling. Meanwhile, extended myocardial fibrosis in TAC mice was also effectively abolished with the administration of AAV9-2J2. Intriguingly, TAC mice display activated TGF-β/Samd-3 signaling with decreased Smad-7 expression, whereas AAV9-2J2 attenuated the phosphorylation of Smad-3 without altering TGF-β expression, whilst preservation of Smad-7. Subsequently, the differentiation of cardiac fibroblasts into myofibroblasts in the presence of TGF-β1 stimulation was significantly disrupted with EET treatment, accompanied by declined Smad-3 activation and collagen production, whereas inhibition of Smad-7 with SiRNA Smad-7 substantially abrogated these effects of EET on cardiac fibroblasts.

CONCLUSIONS:

EET has synergistic actions on cardiomyocytes and cardiac fibroblasts, preventing cardiac hypertrophy through inhibition of Ca2+-mediated calcineurin/NFATc3 signaling cascades, and ameliorating myocardial fibrosis dependent on Smad-7. This work further extends the potential mechanisms of EET, providing a novel therapeutic approach for the treatment of pathological remodeling and heart failure.

• Authors: Xuguang Li, Guang Chu, Feng Zhu, Zhifeng Zheng, Xiang Wang, Guobing Zhang, Fang Wang
• Journal: Experimental cell research (Exp Cell Res) Vol. 386 Issue 1 Pg. 111716 (01 01 2020) ISSN: 1090-2422 [Electronic] United States
• PMID: 31734152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Cardiotonic Agents
• NFATC Transcription Factors
• Smad7 Protein
• Smad7 protein, mouse
• Cytochrome P-450 Enzyme System
• Cytochrome P-450 CYP2J2
• Calcineurin
• 8,11,14-Eicosatrienoic Acid
• Calcium

Topics

• 8,11,14-Eicosatrienoic Acid (pharmacology, therapeutic use)
• Animals
• Calcineurin (metabolism)
• Calcium (metabolism)
• Cardiomegaly (drug therapy, prevention & control)
• Cardiotonic Agents (pharmacology, therapeutic use)
• Cell Line
• Cells, Cultured
• Cytochrome P-450 CYP2J2
• Cytochrome P-450 Enzyme System (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (drug effects, metabolism)
• Myofibroblasts (drug effects, metabolism)
• NFATC Transcription Factors (metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Smad7 Protein (metabolism)