Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, People's Republic of China.
Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, People's Republic of China.
Exp Cell Res. 2020 Jan 1;386(1):111716. doi: 10.1016/j.yexcr.2019.111716. Epub 2019 Nov 14.
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.
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 Ca level and Ca-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.
EET has synergistic actions on cardiomyocytes and cardiac fibroblasts, preventing cardiac hypertrophy through inhibition of Ca-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.
新出现的证据表明，环氧二十碳三烯酸（EETs）作为重要的活性类二十烷酸，调节心血管稳态，但在过压模型中其有利的抗肥厚益处的机制仍不清楚。
在横主动脉缩窄（TAC）后 4 周，TAC 小鼠发生适应性心肌肥厚和随后的心功能衰竭。相反，编码 CYP2J2 的心脏靶向腺相关病毒载体（AAV9）可预防 TAC 诱导的心肌肥厚，保持射血分数。EET 还可防止去甲肾上腺素诱导的 H9c2 心肌细胞肥大。进一步的研究表明，CYP2J2/EET 通过拮抗细胞内 Ca 水平的增加和 Ca 介导的钙调神经磷酸酶/NFATc3 信号发挥对心肌肥厚的保护作用。同时，给予 AAV9-2J2 可有效消除 TAC 小鼠的心肌纤维化。有趣的是，TAC 小鼠显示 TGF-β/Samd-3 信号激活，Smad-7 表达降低，而 AAV9-2J2 可减弱 Smad-3 的磷酸化而不改变 TGF-β的表达，同时保留 Smad-7。随后，在 TGF-β1 刺激下，心肌成纤维细胞向肌成纤维细胞的分化被 EET 治疗显著破坏，伴随着 Smad-3 激活和胶原产生的下降，而用 SiRNA Smad-7 抑制 Smad-7 则可显著削弱 EET 对心肌成纤维细胞的这些作用。
EET 对心肌细胞和心肌成纤维细胞具有协同作用，通过抑制 Ca 介导的钙调神经磷酸酶/NFATc3 信号级联，防止心肌肥厚，并改善依赖 Smad-7 的心肌纤维化。这项工作进一步扩展了 EET 的潜在机制，为病理性重塑和心力衰竭的治疗提供了一种新的治疗方法。
