Intermedin suppresses pressure overload cardiac hypertrophy through activation of autophagy.
Intermedin suppresses pressure overload cardiac hypertrophy through activation of autophagy.
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Intermedin 通过激活自噬抑制压力过载心脏肥大
DOI：
10.1371/journal.pone.0064757
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Jiang W
中科院分区：
文献类型：
--
作者：
Chen H;Wang X;Tong M;Wu D;Wu S;Chen J;Wang X;Wang X;Kang Y;Tang H;Tang C;Jiang W
左心室肥厚是对压力超负荷的适应不良反应，也是心力衰竭的重要危险因素。 Intermedin（IMD）是一种多功能肽，在心血管保护中发挥着重要作用。在这项研究中，我们揭示了一种自噬依赖性机制，该机制参与 IMD 防止心脏重构和心脏肥大时心肌细胞死亡的保护作用。我们观察到，横向主动脉收缩（TAC）诱导、Ang II 或 ISO 暴露分别诱导小鼠心脏和 H9c2 细胞培养物中内源性 IMD 及其受体成分 CRLR、RAMP1 和 RAMP3 的表达显着增加。此外，心脏大小、心脏重量/体重比、心肌细胞大小和细胞凋亡、间质胶原、肥大标志物（包括 ANP 和 BNP 表达）也显着增加，而补充 IMD 可以有效抑制这些增加。此外，IMD 还能诱导毛细血管生成并改善肥厚心脏的功能。我们进一步观察到，IMD 在肥大的心脏和培养细胞中诱导强烈的自噬，这与心肌细胞大小的减小和细胞凋亡是平行的。此外，使用自噬抑制剂3-MA来阻断IMD增强的自噬水平，则IMD对心肌细胞肥大和凋亡的保护作用几乎被消除。我们还观察到补充 IMD 会刺激细胞内 cAMP 的产生，并增强 H9c2 细胞中 Ang II/ISO 暴露诱导的 ERK1/2 磷酸化。此外，我们分别在与 IMD 和 Ang II 或 ISO 共孵育的 H9c2 细胞中使用 wortamannin、H89 和 PD98059 抑制 PI3K、PKA 和 MAPK/ERK1/2 信号通路，并观察到这些抑制剂有效降低了 IMD 增强的自噬水平，但只有 H89 和 PD98059 预孵育消除了 IMD 的抗凋亡作用。洛桑国际管理发展学院。这些结果表明，内源性 IMD 及其受体复合物在肥大的心肌细胞中被诱导，并在心脏肥大的发病机制中发挥重要作用，并且补充 IMD 引起的自噬通过激活 cAMP/PKA 和 MAPK/ERK1/2 途径参与其防止心肌细胞肥大和凋亡。
Left ventricular hypertrophy is a maladaptive response to pressure overload and an important risk factor for heart failure. Intermedin (IMD), a multi-functional peptide, plays important roles in cardiovascular protection. In this study, we revealed an autophagy-dependent mechanism involved in IMD’s protection against cardiac remodeling and cardiomyocyte death in heart hypertrophy. We observed that transverse aortic contraction (TAC) induction, Ang II or ISO exposure induced remarkable increase in the expression of endogenous IMD and its receptor components, CRLR, RAMP1 and RAMP3, in mouse hearts and H9c2 cell cultures, respectively. Furthermore, the heart size, heart weight/body weight ratios, cardiomyocyte size and apoptosis, interstitial collagen, hypertrophic markers including ANP and BNP expression were also significantly increased, which were effectively suppressed by IMD supplementation. In addition, IMD induced capillary angiogenesis and improved functions in hypertrophic hearts. We further observed that IMD induced strong autophagy in hypertrophic hearts and cultured cells, which was paralleling with the decrease in cardiomyocyte size and apoptosis. Furthermore, an autophagy inhibitor, 3-MA, was used to block the IMD-augmented autophagy level, and then the protection of IMD on cardiomyocyte hypertrophy and apoptosis was almost abrogated. We also observed that IMD supplementation stirred intracellular cAMP production, and augmented the ERK1/2 phosphorylation induced by Ang II/ISO exposure in H9c2 cells. In addition, we inhibited PI3K, PKA and MAPK/ERK1/2 signaling pathways by using wortamannin, H89 and PD98059, respectively, in H9c2 cells co-incubating with both IMD and Ang II or ISO, and observed that these inhibitors effectively reduced IMD-augmented autophagy level, but only H89 and PD98059 pre-incubation abrogated the anti-apoptotic action of IMD. These results indicate that the endogenous IMD and its receptor complexes are induced in hypertrophic cardiomyocytes and proposed to play an important role in the pathogenesis of cardiac hypertrophy, and the autophagy stirred by IMD supplementation is involved in its protection against cardiomyocyte hypertrophy and apoptosis through the activation of both cAMP/PKA and MAPK/ERK1/2 pathways.
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