C1q/tumor necrosis factor-related protein-9, a novel adipocyte-derived cytokine, attenuates adverse remodeling in the ischemic mouse heart via protein kinase A activation.
C1q/tumor necrosis factor-related protein-9, a novel adipocyte-derived cytokine, attenuates adverse remodeling in the ischemic mouse heart via protein kinase A activation.
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DOI：
10.1161/circulationaha.112.000010
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发表时间：
2013-09-10
期刊：
影响因子：
37.8
通讯作者：
Ma XL
中科院分区：
文献类型：
--
作者：
Sun Y;Yi W;Yuan Y;Lau WB;Yi D;Wang X;Wang Y;Su H;Wang X;Gao E;Koch WJ;Ma XL
CTRP9是一种新发现的脂联素类似物，具有既定的代谢调节特性。然而，CTRP9在心肌梗死后重构中的作用仍然完全未知。本研究确定C1q/ tnf相关蛋白-9 （CTRP9）是否可能调节急性心肌梗死（AMI）后的心脏重塑，并阐明其潜在机制。雄性成年小鼠经左冠状动脉前降支结扎或假手术致AMI，经腹膜植入渗透泵给予生理盐水（载药）或球状CTRP9治疗6周。体外利用H9C2心肌细胞系确定其潜在机制。AMI后脂肪细胞CTRP9表达及血浆CTRP9水平均显著降低。与对照组相比，CTRP9治疗提高了动物存活率（P<0.05），恢复了心功能（P<0.05），减轻了不良重构（P<0.01），改善了AMI后心肌细胞凋亡和纤维化（P<0.01）。在多种抗重塑分子中，amp激活的蛋白激酶（AMPK）、蛋白激酶-a （PKA）和Akt在ctrp9处理的心脏中被显著激活。令人惊讶的是，CTRP9在心脏特异性AMPK-DN小鼠中仍然具有心脏保护作用。另外，体外实验表明，PKA抑制剂或PKA特异性siRNA几乎消除了CTRP9的抗凋亡作用（P<0.05），而抑制Akt在阻断CTRP9的心脏保护作用方面效果较差。最后，CTRP9磷酸化BAD的多个抗凋亡位点，这一作用被PKA抑制剂阻断。我们证明，脂肪因子CTRP9主要通过pka依赖性途径减轻AMI后的不良心脏重构。
CTRP9 is a newly identified adiponectin paralog with established metabolic-regulatory properties. However, the role of CTRP9 in post-myocardial infarction (post-MI) remodeling remains completely unknown. This study determined whether C1q/TNF-related protein-9 (CTRP9) may regulate cardiac remodeling following acute myocardial infarction (AMI), and elucidated the underlying mechanisms. Male adult mice were subject to AMI by left anterior descending coronary artery (LAD) ligation or sham surgery, and treated with saline (vehicle) or globular CTRP9 via peritoneal implant osmotic-pumps for 6 weeks. H9C2 cardiac cell lines were utilized in vitro for determining underlying mechanisms. Adipocyte CTRP9 expression and plasma CTRP9 levels were both significantly reduced after AMI. Compared to vehicle, CTRP9 treatment improved animal survival rate (P<0.05), restored cardiac function (P<0.05), attenuated adverse remodeling (P<0.01), and ameliorated cardiomyocyte apoptosis and fibrosis following AMI (P<0.01). Among multiple anti-remodeling molecules determined, AMP-activated protein kinase (AMPK), protein kinase-A (PKA), and Akt were significantly activated in CTRP9-treated heart. Surprisingly, CTRP9 remains cardioprotective in cardiac-specific AMPK-DN mice. Additional in vitro experiments demonstrated that administration of either PKA inhibitor or PKA-specific siRNA virtually abolished CTRP9’s anti-apoptotic effect (P<0.05), whereas inhibition of Akt is less effective in blocking CTRP9 cardioprotection. Finally, CTRP9 phosphorylates BAD at its multiple anti-apoptotic sites, an effect blocked by PKA inhibitor. We demonstrate that adipokine CTRP9 attenuates adverse cardiac remodeling following AMI, largely via a PKA-dependent pathway.