NOX4-derived reactive oxygen species limit fibrosis and inhibit proliferation of vascular smooth muscle cells in diabetic atherosclerosis.
NOX4-derived reactive oxygen species limit fibrosis and inhibit proliferation of vascular smooth muscle cells in diabetic atherosclerosis.
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DOI：
10.1016/j.freeradbiomed.2016.07.013
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发表时间：
2016-08
影响因子：
7.4
通讯作者：
Jandeleit-Dahm KAM
中科院分区：
文献类型：
--
作者：
Di Marco E;Gray SP;Kennedy K;Szyndralewiez C;Lyle AN;Lassègue B;Griendling KK;Cooper ME;Schmidt HHHW;Jandeleit-Dahm KAM
平滑肌细胞（SMC）增殖和纤维化有助于晚期动脉粥样硬化病变的发展。活性氧（ROS）产生增加或非生理位置引起的氧化应激是已知的主要病理机制。然而，在动脉粥样硬化中，特别是在高血糖/糖尿病条件下，产生过氧化氢的 NADPH 氧化酶 4 型 (NOX4) 具有保护作用。在这里，我们的目的是阐明血管平滑肌 NOX4 在体内和离体正常和高血糖条件下这种矛盾的动脉粥样硬化保护作用的机制。链脲佐菌素诱导糖尿病 20 周后，与非糖尿病对照组相比，Apoe−/− 小鼠的 SM-α-肌动蛋白和钙调蛋白基因表达降低，同时血小板衍生生长因子 (PDGF)、骨桥蛋白 (OPN) 和细胞外基质 (ECM) 蛋白纤连蛋白表达增加。 Nox4 (Nox4−/− Apoe−/− ) 的基因缺失加剧了糖尿病诱导的 PDGF、OPN、I 型胶原蛋白和增殖标记物 Ki67 的表达。从 NOX4 缺陷小鼠中分离出的主动脉 SMC 表现出去分化表型，包括收缩基因表达丧失、增殖和 ECM 产生增加以及 NOX1 相关 ROS 水平升高。机制研究表明，NOX4 缺陷的 SMC 中 PDGF 信号传导的升高介导了钙调蛋白的丢失和纤连蛋白的增加，而 NOX1 的上调与 OPN 和增殖标志物表达的增加有关。这些发现表明，NOX4 通过 PDGF 和 NOX1 的活性，积极调节糖尿病 Apoe−/− 小鼠和原代小鼠 SMC 中的 SMC 病理生理反应。
Smooth muscle cell (SMC) proliferation and fibrosis contribute to the development of advanced atherosclerotic lesions. Oxidative stress caused by increased production or unphysiological location of reactive oxygen species (ROS) is a known major pathomechanism. However, in atherosclerosis, in particular under hyperglycaemic/diabetic conditions, the hydrogen peroxide-producing NADPH oxidase type 4 (NOX4) is protective. Here we aim to elucidate the mechanisms underlying this paradoxical atheroprotection of vascular smooth muscle NOX4 under conditions of normoand hyperglycaemia both in vivo and ex vivo. Following 20-weeks of streptozotocin-induced diabetes, Apoe−/− mice showed a reduction in SM-alpha-actin and calponin gene expression with concomitant increases in platelet-derived growth factor (PDGF), osteopontin (OPN) and the extracellular matrix (ECM) protein fibronectin when compared to non-diabetic controls. Genetic deletion of Nox4 (Nox4−/− Apoe−/− ) exacerbated diabetes-induced expression of PDGF, OPN, collagen I, and proliferation marker Ki67. Aortic SMCs isolated from NOX4-deficient mice exhibited a dedifferentiated phenotype including loss of contractile gene expression, increased proliferation and ECM production as well as elevated levels of NOX1-associated ROS. Mechanistic studies revealed that elevated PDGF signalling in NOX4-deficient SMCs mediated the loss of calponin and increase in fibronectin, while the upregulation of NOX1 was associated with the increased expression of OPN and markers of proliferation. These findings demonstrate that NOX4 actively regulates SMC pathophysiological responses in diabetic Apoe−/− mice and in primary mouse SMCs through the activities of PDGF and NOX1.