From the Department of Cardiovascular Medicine (H.S., K.E., K.F., S.M., M.S., I.K., I.M.), Translational Systems Biology and Medicine Initiative (K.F.), Graduate School of Medicine, and Graduate School of Pharmaceutical Sciences (N.K., H.A.), The University of Tokyo, Tokyo, Japan; Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (Y.O.-T.); and Jichi Medical University, Tochigi, Japan (R.N.).
Arterioscler Thromb Vasc Biol. 2013 Nov;33(11):2596-607. doi: 10.1161/ATVBAHA.113.302099. Epub 2013 Aug 22.
Obesity is a major risk factor of atherosclerotic cardiovascular disease. Circulating free fatty acid levels are known to be elevated in obese individuals and, along with dietary saturated fatty acids, are known to associate with cardiovascular events. However, little is known about the molecular mechanisms by which free fatty acids are linked to cardiovascular disease.
We found that administration of palmitate, a major saturated free fatty acid, to mice markedly aggravated neointima formation induced by carotid artery ligation and that the neointima primarily consisted of phenotypically modulated smooth muscle cells (SMCs). In cultured SMCs, palmitate-induced phenotypic modulation was characterized by downregulation of SMC differentiation markers, such as SM α-actin and SM-myosin heavy chain, and upregulation of mediators involved in inflammation and remodeling of the vessel wall, such as platelet-derived growth factor B and matrix metalloproteinases. We also found that palmitate induced the expression of proinflammatory genes via a novel toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor-κB/NADPH oxidase 1/reactive oxygen species signaling pathway: nuclear factor-κB was activated by palmitate via toll-like receptor 4 and its adapter, MyD88, and once active, it transactivated Nox1, encoding NADPH oxidase 1, a major reactive oxygen species generator in SMCs. Pharmacological inhibition and small interfering RNA-mediated knockdown of the components of this signaling pathway mitigated the palmitate-induced upregulation of proinflammatory genes. More importantly, Myd88 knockout mice were resistant to palmitate-induced exacerbation of neointima formation.
Palmitate seems to promote neointima formation by inducing inflammatory phenotypes in SMCs.
肥胖是动脉粥样硬化性心血管疾病的一个主要危险因素。已知肥胖个体的循环游离脂肪酸水平升高，并且与膳食饱和脂肪酸一起，与心血管事件相关。然而，对于游离脂肪酸与心血管疾病相关的分子机制知之甚少。
我们发现，给小鼠施用棕榈酸（一种主要的饱和游离脂肪酸）可显著加剧颈动脉结扎引起的新生内膜形成，而新生内膜主要由表型调节的平滑肌细胞（SMC）组成。在培养的 SMC 中，棕榈酸诱导的表型调节表现为 SMC 分化标志物如 SM α-肌动蛋白和 SM-肌球蛋白重链的下调，以及参与炎症和血管壁重塑的介质如血小板衍生生长因子 B 和基质金属蛋白酶的上调。我们还发现，棕榈酸通过一种新的 Toll 样受体 4/髓样分化初级反应 88/核因子-κB/NADPH 氧化酶 1/活性氧信号通路诱导促炎基因的表达：核因子-κB 通过 Toll 样受体 4 及其衔接子 MyD88 被棕榈酸激活，一旦激活，它就会反式激活编码 NADPH 氧化酶 1 的 Nox1，NADPH 氧化酶 1 是 SMC 中主要的活性氧生成酶。该信号通路的药理学抑制和小干扰 RNA 介导的敲低减轻了棕榈酸诱导的促炎基因的上调。更重要的是，Myd88 敲除小鼠对棕榈酸诱导的新生内膜形成加剧具有抗性。
棕榈酸似乎通过诱导 SMC 中的炎症表型促进新生内膜形成。
