Significance of the transcription factor KLF5 in cardiovascular remodeling
Significance of the transcription factor KLF5 in cardiovascular remodeling
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DOI：
10.1111/j.1538-7836.2005.01366.x
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发表时间：
2005-08-01
影响因子：
10.4
通讯作者：
Manabe, I
中科院分区：
文献类型：
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作者：
Nagai, R;Suzuki, T;Manabe, I
心脏和血管的结构重塑是许多心血管疾病发展中的重要病理过程。然而，在心血管重塑过程中改变基因表达的转录调控还没有很好地理解。我们以前分离KLF 5/基本转录元件结合（BTEB）2，Kruppel样因子，作为一个转录因子，结合胚胎平滑肌肌球蛋白重链基因（SMemb）的启动子。KLF 5激活心血管重塑过程中可诱导的许多基因，如血小板衍生生长因子（PDGF）-A/B、Egr-1、纤溶酶原激活物抑制剂-1（派-1）、诱导型一氧化氮合酶（iNOS）和血管内皮生长因子（VEGF）受体。KLF 5在胚胎平滑肌中大量表达，并随着血管发育而下调，但在血管损伤后增殖的新生内膜平滑肌中重新表达。在KLF 5基因靶向小鼠中，纯合子在早期胚胎阶段死亡，而杂合子显然是正常的。然而，在应对外部压力，动脉的杂合子表现出减少水平的平滑肌和外膜细胞的激活。此外，血管紧张素II诱导的心脏肥大和纤维化在杂合子中减弱。KLF 5活性受许多转录调节因子和核受体调节，如视黄酸受体-α（RAR α）、NF-κ B、PPAR γ、p300和SET。有趣的是，RAR α激动剂抑制KLF 5和心血管重塑，而RA R α拮抗剂激活KLF 5并诱导血管生成。这些结果表明KLF 5是心血管重构中的一个重要转录因子，是心血管疾病的潜在治疗靶点。
Structural remodeling of the heart and blood vessels is an important pathologic process in the development of many cardiovascular diseases. However, transcriptional regulation of altered gene expression during cardiovascular remodeling is not well understood. We previously isolated KLF5/basic transcription element-binding (BTEB)2, a Kruppel-like factor, as a transcription factor that binds the promoter of the embryonic smooth muscle myosin heavy chain gene (SMemb). KLF5 activates many genes inducible during cardiovascular remodeling, such as platelet-derived growth factor (PDGF)-A/B, Egr-1, plasminogen activator inhibitor-1 (PAI-1), inducible nitric oxide synthase (iNOS), and vascular endothelial growth factor (VEGF) receptors. KLF5 is abundantly expressed in embryonic smooth muscles and is down-regulated with vascular development, but reinduced in proliferative neointimal smooth muscles in response to vascular injury. In KLF5 gene-targeted mice, homozygotes die at an early embryonic stage whereas heterozygotes are apparently normal. However, in response to external stress, arteries of heterozygotes exhibit diminished levels of smooth muscle and adventitial cell activation. Furthermore, angiotensin II-induced cardiac hypertrophy and fibrosis are attenuated in heterozygotes. KLF5 activities are regulated by many transcriptional regulators and nuclear receptors, such as retinoic acid receptor-alpha (RAR alpha), NF-kappa B, PPAR gamma, p300, and SET. Interestingly, RAR alpha agonist suppresses KLF5 and cardiovascular remodeling, whereas RA R alpha antagonist activates KLF5 and induces angiogenesis. These results indicate that KLF5 is an essential transcription factor in cardiovascular remodeling and a potential therapeutic target for cardiovascular disease.