HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced "inside-out" signaling to extracellular matrix by preventing RhoA activation.
HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced "inside-out" signaling to extracellular matrix by preventing RhoA activation.
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HMG-CoA 还原酶抑制剂辛伐他汀通过阻止 RhoA 激活来减轻 VEGF 诱导的细胞外基质“由内而外”信号传导。
DOI：
10.1152/ajprenal.00092.2006
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Danesh,FarhadR
中科院分区：
文献类型：
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作者：
Xu,Hanshi;Zeng,Lixia;Peng,Hui;Chen,Sheldon;Jones,Jonathan;Chew,Teng-Leong;Sadeghi,MehranM;Kanwar,YashpalS;Danesh,FarhadR
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂通过阻止甲羟戊酸途径衍生的各种类异戊二烯的合成，对许多细胞信号传导级联发挥调节作用。在本研究中，我们描述了HMG-CoA还原酶抑制剂（通常称为他汀类药物）对血管内皮生长因子（VEGF）诱导的IV型胶原积累的一种新型多效性作用。VEGF是一种血管生成多肽，也已知其在内皮细胞渗透性和分化中起重要作用。最近，VEGF也被牵连在促进细胞外基质（ECM）的积累，虽然精确的信号传导机制，介导VEGF诱导的ECM扩张仍然很差的特点。阐明VEGF对ECM发挥作用的机制显然是理解这种分子的复杂生物学以及在几种病理过程中靶向VEGF的先决条件。为此，本研究探讨了介导VEGF诱导的系膜细胞ECM扩增的潜在分子机制。我们的研究结果表明，VEGF刺激引起ECM积累的强烈增加，涉及RhoA激活，完整的肌动蛋白细胞骨架和β1-整合素激活。我们的数据还表明，辛伐他汀，通过甲羟戊酸消耗，逆转VEGF诱导的ECM积累，防止RhoA激活。
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert modulatory effects on a number of cell signaling cascades by preventing the synthesis of various isoprenoids derived from the mevalonate pathway. In the present study, we describe a novel pleiotropic effect of HMG-CoA reductase inhibitors, also commonly known as statins, on vascular endothelial growth factor (VEGF)-induced type IV collagen accumulation. VEGF is an angiogenic polypeptide that is also known to play a central role in endothelial cell permeability and differentiation. Recently, VEGF has also been implicated in promoting extracellular matrix (ECM) accumulation, although the precise signaling mechanism that mediates VEGF-induced ECM expansion remains poorly characterized. Elucidation of the mechanisms through which VEGF exerts its effect on ECM is clearly a prerequisite for both understanding the complex biology of this molecule as well as targeting VEGF in several pathological processes. To this end, this study explored the underlying molecular mechanisms mediating VEGF-induced ECM expansion in mesangial cells. Our findings show that VEGF stimulation elicits a robust increase in ECM accumulation that involves RhoA activation, an intact actin cytoskeleton, and β1- integrin activation. Our data also indicate that simvastatin, via mevalonate depletion, reverses VEGF-induced ECM accumulation by preventing RhoA activation.