Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China, 510080.
Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, Guangdong, China, 510080.
Biosci Rep. 2019 Jul 29;39(7). doi: 10.1042/BSR20171358. Print 2019 Jul 31.
Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional secreted protein that can be induced by fasting, hypoxia and glucocorticoids. ANGPTL4 has been associated with a variety of diseases; however, the role of ANGPTL4 in cardiac hypertrophy remains poorly understood. In our study, we aimed to explore the effect of ANGPTL4 on phenylephrine-induced cardiomyocyte hypertrophy. Our results showed that knockdown of ANGPTL4 expression significantly exacerbated cardiomyocyte hypertrophy, as demonstrated by increased hypertrophic marker expression, including ANP and cell surface area. Moreover, significantly reduced fatty acid oxidation, as featured by decreased CPT-1 levels, was observed in hypertrophic cardiomyocytes following ANGPTL4 down-regulation. Furthermore, knockdown of ANGPLT4 led to down-regulated expression of peroxisome proliferator-activated receptor α (PPARα), which is the key regulator of cardiac fatty acid oxidation. In addition, ANGPTL4 silencing promoted the activation of JNK1/2, and JNK1/2 signaling blockade could restore the level of PPARα and significantly ameliorate the ANGPTL4 knockdown-induced cardiomyocyte hypertrophy. Therefore, our study demonstrated that ANGPTL4 regulates PPARα through JNK1/2 signaling and is required for the inhibition of cardiomyocyte hypertrophy.
血管生成素样蛋白 4（ANGPTL4）是一种多功能分泌蛋白，可被禁食、缺氧和糖皮质激素诱导。ANGPTL4 与多种疾病有关；然而，ANGPTL4 在心肌肥厚中的作用仍知之甚少。在我们的研究中，我们旨在探讨 ANGPTL4 对苯肾上腺素诱导的心肌细胞肥大的影响。我们的结果表明，ANGPTL4 表达的敲低显著加剧了心肌细胞肥大，表现为肥大标志物的表达增加，包括 ANP 和细胞表面积。此外，在 ANGPTL4 下调后，肥大心肌细胞中的脂肪酸氧化明显减少，表现为 CPT-1 水平降低。此外，ANGPLT4 的敲低导致过氧化物酶体增殖物激活受体 α（PPARα）的表达下调，PPARα 是心脏脂肪酸氧化的关键调节因子。此外，ANGPTL4 沉默促进了 JNK1/2 的激活，而 JNK1/2 信号通路的阻断可以恢复 PPARα 的水平，并显著改善 ANGPTL4 敲低诱导的心肌细胞肥大。因此，我们的研究表明，ANGPTL4 通过 JNK1/2 信号通路调节 PPARα，是抑制心肌细胞肥大所必需的。
