Helix-loop-helix protein p8, a transcriptional regulator required for cardiomyocyte hypertrophy and cardiac fibroblast matrix metalloprotease induction
Helix-loop-helix protein p8, a transcriptional regulator required for cardiomyocyte hypertrophy and cardiac fibroblast matrix metalloprotease induction
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DOI：
10.1128/mcb.00996-06
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发表时间：
2007-02-01
影响因子：
5.3
通讯作者：
Kyriakis, John M.
中科院分区：
文献类型：
--
作者：
Goruppi, Sandro;Patten, Richard D.;Kyriakis, John M.
心肌细胞肥大和细胞外基质重塑，主要由炎性酪氨酸刺激的心脏成纤维细胞介导，是心脏病理学中的关键细胞事件。控制这些过程的分子成分仍然模糊不清，很少有基因与肥大和基质重塑有关。在这里，我们表明，p8，一个小的应激诱导的基本螺旋环螺旋蛋白，是必需的内皮素和α-肾上腺素能激动剂诱导的心肌细胞肥大和肿瘤坏死因子刺激诱导，在心脏成纤维细胞，基质金属蛋白酶（MMPs）9和13-MMPs与一般炎症和不良的心室重构心力衰竭。p8以刺激依赖的方式与含有c-Jun的染色质、心肌细胞心房利钠因子（anf）启动子、心脏成纤维细胞mmp 9和mmp 13启动子（已建立激活蛋白1效应子）相关。在衰竭的人心脏中，通过治疗干预逆转的过程也强烈诱导p8。我们的研究结果确定了一个意想不到的广泛参与p8在关键的细胞事件与心肌细胞肥大和心脏成纤维细胞MMP的生产，这两个发生在心力衰竭。
Cardiomyocyte hypertrophy and extracellular matrix remodeling, primarily mediated by inflammatory cytokine-stimulated cardiac fibroblasts, are critical cellular events in cardiac pathology. The molecular components governing these processes remain nebulous, and few genes have been linked to both hypertrophy and matrix remodeling. Here we show that p8, a small stress-inducible basic helix-loop-helix protein, is required for endothelin- and alpha-adrenergic agonist-induced cardiomyocyte hypertrophy and for tumor necrosis factor-stimulated induction, in cardiac fibroblasts, of matrix metalloproteases (MMPs) 9 and 13-MMPs linked to general inflammation and to adverse ventricular remodeling in heart failure. In a stimulus-dependent manner, p8 associates with chromatin containing c-Jun and with the cardiomyocyte atrial natriuretic factor (anf) promoter and the cardiac fibroblast mmp9 and mmp13 promoters, established activator protein 1 effectors. p8 is also induced strongly in the failing human heart by a process reversed upon therapeutic intervention. Our results identify an unexpectedly broad involvement for p8 in key cellular events linked to cardiomyocyte hypertrophy and cardiac fibroblast MMP production, both of which occur in heart failure.