Endothelial Klf2-Foxp1-TGFβ signal mediates the inhibitory effects of simvastatin on maladaptive cardiac remodeling.
Endothelial Klf2-Foxp1-TGFβ signal mediates the inhibitory effects of simvastatin on maladaptive cardiac remodeling.
复制标题
内皮 Klf2-Foxp1-TGFβ 信号介导辛伐他汀对适应不良心脏重塑的抑制作用。
作者：
Li H;Wang Y;Liu J;Chen X;Duan Y;Wang X;Shen Y;Kuang Y;Zhuang T;Tomlinson B;Chan P;Yu Z;Cheng Y;Zhang L;Liu Z;Zhang Y;Zhao Z;Zhang Q;Liu J
目的：病理性心脏纤维化和肥厚是左心室重塑的常见特征，通常会发展为心力衰竭（HF）。内皮细胞（EC）是成年小鼠心脏中最丰富的非肌细胞细胞。辛伐他汀是血管内皮细胞克鲁珀尔样因子 2（Klf2）的强诱导剂，能改善压力过载引起的适应性不良心脏重塑和功能障碍。本研究旨在探索辛伐他汀抗重塑作用的详细分子机制。
方法与结果我们发现辛伐他汀在体内抑制EC-Klf2后对压力过载诱导的适应性不良心脏重塑和功能障碍没有保护作用。机制研究表明，抑制EC-Klf2可逆转辛伐他汀介导的成纤维细胞增殖和肌成纤维细胞形成的减少，以及心肌细胞大小和心脏肥大基因的减少，这表明EC-Klf2可能介导了辛伐他汀的抗纤维化和抗肥大作用。在培养的EC中抑制Klf2后也观察到了类似的效应。此外，Klf2 还能调节心血管内的直接靶基因 TGFβ1，并介导辛伐他汀的保护作用，而抑制 EC-Klf2 会增加 EC-TGFβ1 的表达，导致辛伐他汀失去保护作用。此外，EC-Klf2还能调节EC-Foxp1，EC-Foxp1的缺失会减弱辛伐他汀的保护作用，这与抑制EC-Klf2的作用类似。
结论：我们得出结论：心脏微血管心电子元件在调节压力过载诱导的不良心脏重塑和功能障碍中具有重要作用，而内皮 Klf2-TGFβ1 或 Klf2-Foxp1-TGFβ1 通路介导了辛伐他汀的预防作用。这项研究证明了辛伐他汀预防高血压的非降胆固醇作用的新机制。
Aims: Pathological cardiac fibrosis and hypertrophy are common features of left ventricular remodeling that often progress to heart failure (HF). Endothelial cells (ECs) are the most abundant non-myocyte cells in adult mouse heart. Simvastatin, a strong inducer of Krüppel-like Factor 2 (Klf2) in ECs, ameliorates pressure overload induced maladaptive cardiac remodeling and dysfunction. This study aims to explore the detailed molecular mechanisms of the anti-remodeling effects of simvastatin. Methods and Results: RGD-magnetic-nanoparticles were used to endothelial specific delivery of siRNA and we found absence of simvastatin's protective effect on pressure overload induced maladaptive cardiac remodeling and dysfunction after in vivo inhibition of EC-Klf2. Mechanism studies showed that EC-Klf2 inhibition reversed the simvastatin-mediated reduction of fibroblast proliferation and myofibroblast formation, as well as cardiomyocyte size and cardiac hypertrophic genes, which suggested that EC-Klf2 might mediate the anti-fibrotic and anti-hypertrophy effects of simvastatin. Similar effects were observed after Klf2 inhibition in cultured ECs. Moreover, Klf2 regulated its direct target gene TGFβ1 in ECs and mediated the protective effects of simvastatin, and inhibition of EC-Klf2 increased the expression of EC-TGFβ1 leading to simvastatin losing its protective effects. Also, EC-Klf2 was found to regulate EC-Foxp1 and loss of EC-Foxp1 attenuated the protective effects of simvastatin similar to EC-Klf2 inhibition. Conclusions: We conclude that cardiac microvasculature ECs are important in the modulation of pressure overload induced maladaptive cardiac remodeling and dysfunction, and the endothelial Klf2-TGFβ1 or Klf2-Foxp1-TGFβ1 pathway mediates the preventive effects of simvastatin. This study demonstrates a novel mechanism of the non-cholesterol lowering effects of simvastatin for HF prevention.
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影响因子：
20.1
作者：
Pinto AR;Ilinykh A;Ivey MJ;Kuwabara JT;D'Antoni ML;Debuque R;Chandran A;Wang L;Arora K;Rosenthal NA;Tallquist MD
通讯作者：
Tallquist MD
DOI：
10.1038/nrm3495
发表时间：
2013-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
8.7
作者：
Dong, QG;Bernasconi, S;Vecchi, A
通讯作者：
Vecchi, A
影响因子：
24.5
作者：
Marrone, Giusi;Maeso-Diaz, Raquel;Gracia-Sancho, Jordi
通讯作者：
Gracia-Sancho, Jordi
影响因子：
39.3
作者：
Preiss D;Campbell RT;Murray HM;Ford I;Packard CJ;Sattar N;Rahimi K;Colhoun HM;Waters DD;LaRosa JC;Amarenco P;Pedersen TR;Tikkanen MJ;Koren MJ;Poulter NR;Sever PS;Ridker PM;MacFadyen JG;Solomon SD;Davis BR;Simpson LM;Nakamura H;Mizuno K;Marfisi RM;Marchioli R;Tognoni G;Athyros VG;Ray KK;Gotto AM;Clearfield MB;Downs JR;McMurray JJ
通讯作者：
McMurray JJ