Inhibition of CTRP9, a novel and cardiac-abundantly expressed cell survival molecule, by TNFα-initiated oxidative signaling contributes to exacerbated cardiac injury in diabetic mice.
Inhibition of CTRP9, a novel and cardiac-abundantly expressed cell survival molecule, by TNFα-initiated oxidative signaling contributes to exacerbated cardiac injury in diabetic mice.
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DOI：
10.1007/s00395-012-0315-z
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发表时间：
2013-01
影响因子：
9.5
通讯作者：
Ma XL
中科院分区：
文献类型：
--
作者：
Su H;Yuan Y;Wang XM;Lau WB;Wang Y;Wang X;Gao E;Koch WJ;Ma XL
C1q/ tnf相关蛋白（CTRPs）最近被确定为脂联素（APN）的类似物，与APN具有相似的代谢调节功能。本研究确定了心脏CTRP的表达及其潜在的心脏保护功能，并研究糖尿病是否以及如何调节心脏CTRP的表达。一些CTRPs在心脏中的表达水平明显高于APN。最值得注意的是，与APN最相似的CTRP9在心脏的表达超过APN 100倍。在高脂肪饮食诱导的糖尿病小鼠中，心脏CTRP9的表达显著降低。在H9c2细胞中，肿瘤坏死因子-α (TNF-α)强烈抑制CTRP9的表达（bbb60 %），并显著降低过氧化物酶体增殖物激活受体- γ (PPARγ)，一种已知的促进脂联素表达的转录因子。TNF-α对PPARγ和CTRP9的抑制作用被铁或罗格列酮逆转。CTRP9敲低显著增强，而CTRP9过表达显著减轻H9c2细胞模拟缺血再灌注损伤。在糖尿病小鼠体内给药CTRP9可显著降低NADPH氧化酶的表达和超氧化物的产生，减少梗死面积，改善心功能。据我们所知，这是第一个提供证据的研究，证明通过TNF-α-启动的氧化PPARγ抑制CTRP9（一种在心脏中丰富表达的新型细胞存活分子）的下调有助于加重糖尿病心脏损伤。维持CTRP9的表达或增强CTRP9启动的信号机制可能是改善缺血性糖尿病心脏损伤的潜在途径。
Recently identified as adiponectin (APN) paralogs, C1q/TNF-related proteins (CTRPs) share similar metabolic regulatory functions as APN. The current study determined cardiac expression of CTRPs, their potential cardioprotective function, and investigated whether and how diabetes may regulate cardiac CTRP expression. Several CTRPs are expressed in the heart at levels significantly greater than APN. Most notably, cardiac expression of CTRP9, the closest paralog of APN, exceeds APN by >100-fold. Cardiac CTRP9 expression was significantly reduced in high-fat diet-induced diabetic mice. In H9c2 cells, tumor necrosis factor-alpha (TNF-α) strongly inhibited CTRP9 expression (>60 %), and significantly reduced peroxisome proliferator activated receptor-gamma (PPARγ), a known transcription factor promoting adiponectin expression. The inhibitory effect of TNF-α on PPARγ and CTRP9 was reversed by Tiron or rosiglitazone. CTRP9 knockdown significantly enhanced, whereas CTRP9 overexpression significantly attenuated simulated ischemia/reperfusion injury in H9c2 cells. In vivo CTRP9 administration to diabetic mice significantly attenuated NADPH oxidase expression and superoxide generation, reduced infarct size, and improved cardiac function. To the best of our knowledge, this is the first study providing evidence that down-regulation of CTRP9, an abundantly expressed and novel cell survival molecule in the heart, by TNF-α-initiated oxidative PPARγ suppression contributes to exacerbated diabetic cardiac injury. Preservation of CTRP9 expression or augmentation of CTRP9-initiated signaling mechanisms may be the potential avenues for ameliorating ischemic diabetic cardiac injury.
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TNFα独立于其细胞表面受体保护心脏线粒体。
影响因子：
9.5
作者：
Lacerda L;McCarthy J;Mungly SF;Lynn EG;Sack MN;Opie LH;Lecour S
通讯作者：
Lecour S
DOI：
10.1073/pnas.0403760101
发表时间：
2004-07-13
影响因子：
11.1
作者：
Wong, GW;Wang, J;Lodish, HF
通讯作者：
Lodish, HF
DOI：
10.1073/pnas.2536828100
发表时间：
2003-12-23
影响因子：
11.1
作者：
He, WM;Barak, Y;Evans, RM
通讯作者：
Evans, RM
影响因子：
82.9
作者：
Maeda, N;Shimomura, I;Matsuzawa, Y
通讯作者：
Matsuzawa, Y
影响因子：
82.9
作者：
Shibata, R;Sato, K;Walsh, K
通讯作者：
Walsh, K