C1q-TNF-Related Protein-9 Promotes Cardiac Hypertrophy and Failure
C1q-TNF-Related Protein-9 Promotes Cardiac Hypertrophy and Failure
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DOI：
10.1161/circresaha.116.309398
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发表时间：
2017-01-06
影响因子：
20.1
通讯作者：
Heineke, Joerg
中科院分区：
文献类型：
--
作者：
Appari, Mahesh;Breitbart, Astrid;Heineke, Joerg
原理：心肌内皮细胞促进心肌细胞肥大，可能通过释放生长因子。这些因素的身份，然而，在很大程度上仍然未知，我们假设在这里分泌的CTRP 9（C1 q-肿瘤坏死因子相关蛋白-9）可能作为内皮衍生蛋白来调节心脏重构在responsible to pressure overload.Objective：检查心脏CTRP 9的来源和它的功能在压力overload.Methods和结果：CTRP 9主要来自心肌毛细血管内皮细胞。CTRP 9 mRNA的表达在肥厚的人类心脏和小鼠心脏后，横向主动脉缩窄（TAC）增强。CTRP 9蛋白在重度主动脉瓣狭窄患者血清和TAC后小鼠心脏中更丰富。有趣的是，杂合子，特别是纯合子敲除C1 qtnf 9（CTRP 9）基因缺失的小鼠在TAC期间免受心脏肥大，左心室扩张和功能障碍的发展。CTRP 9过表达反过来促进小鼠TAC后的肥厚性心脏重塑和功能障碍，并诱导分离的成年心肌细胞肥大。从机制上讲，与野生型小鼠相比，CTRP 9敲除小鼠在TAC期间显示出活化的促肥大ERK 5（细胞外信号调节激酶5）水平显著降低，而CTRP 9过表达则导致响应压力超负荷的ERK 5活化增加。通过显性失活MEK 5突变体或通过ERK 5/MEK 5抑制剂BIX 02189钝化的CTRP 9抑制ERK 5在体外引发分离的成年心肌细胞肥大，并分别在体内减弱小鼠心肌细胞肥大和心功能障碍。下游的ERK 5，我们确定了促肥大转录因子GATA 4，这是直接激活通过ERK 5依赖的磷酸化。结论：CTRP 9的上调肥厚性心脏病促进适应不良的心脏重塑和左心室功能障碍，并可能构成一个治疗目标，在未来。
Rationale: Myocardial endothelial cells promote cardiomyocyte hypertrophy, possibly through the release of growth factors. The identity of these factors, however, remains largely unknown, and we hypothesized here that the secreted CTRP9 (C1q-tumor necrosis factor-related protein-9) might act as endothelial-derived protein to modulate heart remodeling in response to pressure overload.Objective: To examine the source of cardiac CTRP9 and its function during pressure overload.Methods and Results: CTRP9 was mainly derived from myocardial capillary endothelial cells. CTRP9 mRNA expression was enhanced in hypertrophic human hearts and in mouse hearts after transverse aortic constriction (TAC). CTRP9 protein was more abundant in the serum of patients with severe aortic stenosis and in murine hearts after TAC. Interestingly, heterozygous and especially homozygous knock-out C1qtnf9 (CTRP9) gene-deleted mice were protected from the development of cardiac hypertrophy, left ventricular dilatation, and dysfunction during TAC. CTRP9 overexpression, in turn, promoted hypertrophic cardiac remodeling and dysfunction after TAC in mice and induced hypertrophy in isolated adult cardiomyocytes. Mechanistically, CTRP9 knock-out mice showed strongly reduced levels of activated prohypertrophic ERK5 (extracellular signal-regulated kinase 5) during TAC compared with wild-type mice, while CTRP9 overexpression entailed increased ERK5 activation in response to pressure overload. Inhibition of ERK5 by a dominant negative MEK5 mutant or by the ERK5/MEK5 inhibitor BIX02189 blunted CTRP9 triggered hypertrophy in isolated adult cardiomyocytes in vitro and attenuated mouse cardiomyocyte hypertrophy and cardiac dysfunction in vivo, respectively. Downstream of ERK5, we identified the prohypertrophic transcription factor GATA4, which was directly activated through ERK5-dependent phosphorylation.Conclusions: The upregulation of CTRP9 during hypertrophic heart disease facilitates maladaptive cardiac remodeling and left ventricular dysfunction and might constitute a therapeutic target in the future.