Fukuda Kazuki, Matsumura Takeshi, Senokuchi Takafumi, Ishii Norio, Kinoshita Hiroyuki, Yamada Sarie, Murakami Saiko, Nakao Saya, Motoshima Hiroyuki, Kondo Tatsuya, Kukidome Daisuke, Kawasaki Shuji, Kawada Teruo, Nishikawa Takeshi, Araki Eiichi
Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Biochem Biophys Res Commun. 2015 Jan 30;457(1):23-30. doi: 10.1016/j.bbrc.2014.12.063. Epub 2014 Dec 19.
The peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARγ in macrophages. However, it is not yet known whether statins activate PPARγ in other vascular cells. In the present study, we investigated whether statins activate PPARγ in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARγ in HASMCs, but not in HUVECs. Statins induced cyclooxygenase-2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2-siRNA abrogated statin-mediated PPARγ activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in HASMCs. These effects of statins were abrogated by treatment with PPARγ-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe(-/-) mice. In addition, transcriptional activity of PPARγ and CD36 expression were increased, and the expression of MCP-1 and TNF-α was decreased, in the aorta of statin-treated Apoe(-/-) mice. In conclusion, statins mediate anti-atherogenic effects through PPARγ activation in SMCs. These effects of statins on SMCs may be beneficial for the prevention of atherosclerosis.
过氧化物酶体增殖物激活受体γ（PPARγ）是脂质和葡萄糖代谢的重要调节因子，据报道其激活可抑制动脉粥样硬化的进展。我们曾报道3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）可在巨噬细胞中激活PPARγ。然而，尚不清楚他汀类药物是否能在其他血管细胞中激活PPARγ。在本研究中，我们调查了他汀类药物是否能在平滑肌细胞（SMC）和内皮细胞（EC）中激活PPARγ，从而介导抗动脉粥样硬化作用。本研究使用了人主动脉平滑肌细胞（HASMC）和人脐静脉内皮细胞（HUVEC）。氟伐他汀和匹伐他汀可在HASMC中激活PPARγ，但在HUVEC中则不能。他汀类药物可诱导HASMC中环氧合酶-2（COX-2）的表达，但在HUVEC中则不能。此外，用COX-2小干扰RNA（siRNA）处理可消除他汀类药物介导的HASMC中PPARγ的激活。他汀类药物可抑制HASMC的迁移和增殖，并抑制脂多糖诱导的HASMC中单核细胞趋化蛋白-1（MCP-1）和肿瘤坏死因子-α（TNF-α）的表达。用PPARγ-siRNA处理可消除他汀类药物的这些作用。用他汀类药物处理可抑制载脂蛋白E基因敲除（Apoe(-/-)）小鼠的动脉粥样硬化病变形成。此外，在他汀类药物处理的Apoe(-/-)小鼠的主动脉中，PPARγ的转录活性和CD36的表达增加，而MCP-1和TNF-α的表达减少。总之，他汀类药物通过在SMC中激活PPARγ介导抗动脉粥样硬化作用。他汀类药物对SMC的这些作用可能对预防动脉粥样硬化有益。
