Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1598-605. doi: 10.1161/ATVBAHA.109.202309. Epub 2010 May 27.
Nifedipine, an L-type calcium channel blocker, protects against the progression of atherosclerosis. We investigated the molecular basis of the antiatherosclerotic effect of nifedipine in macrophages and apolipoprotein E-deficient mice.
In macrophages, nifedipine increased peroxisome proliferator-activated receptor-gamma (PPARgamma) activity without increasing PPARgamma-binding activity. Amlodipine, another L-type calcium channel blocker, and 1,2-bis-(o-aminophenoxy)-ethane-N,N,-N',N'-tetraacetic acid tetraacetoxy-methyl ester (BAPTA-AM), a calcium chelator, decreased PPARgamma activity, suggesting that nifedipine does not activate PPARgamma via calcium channel blocker activity. Inactivation of extracellular signal-regulated kinase 1/2 suppressed PPARgamma2-Ser112 phosphorylation and induced PPARgamma activation. Nifedipine suppressed extracellular signal-regulated kinase 1/2 activation and PPARgamma2-Ser112 phosphorylation, and mutating PPARgamma2-Ser112 to Ala abrogated nifedipine-mediated PPARgamma activation. These results suggested that nifedipine inhibited extracellular signal-regulated kinase 1/2 activity and PPARgamma2-Ser112 phosphorylation, leading to PPARgamma activation. Nifedipine inhibited lipopolysaccharide-induced monocyte chemoattractant protein-1 expression and induced ATP-binding cassette transporter A1 mRNA expression, and these effects were abrogated by small interfering RNA for PPARgamma. Furthermore, in apolipoprotein E-deficient mice, nifedipine treatment decreased atherosclerotic lesion size, phosphorylation of PPARgamma2-Ser112 and extracellular signal-regulated kinase 1/2, and monocyte chemoattractant protein-1 mRNA expression and increased ATP-binding cassette transporter A1 expression in the aorta.
Nifedipine unlike amlodipine inhibits PPARgamma-Ser phosphorylation and activates PPARgamma to suppress monocyte chemoattractant protein-1 expression and induce ATP-binding cassette transporter A1 expression in macrophages. These effects may induce antiatherogenic effects in hypertensive patients.
硝苯地平是一种 L 型钙通道阻滞剂，可防止动脉粥样硬化进展。我们研究了硝苯地平在巨噬细胞和载脂蛋白 E 缺陷小鼠中抗动脉粥样硬化作用的分子基础。
在巨噬细胞中，硝苯地平增加过氧化物酶体增殖物激活受体-γ（PPARγ）的活性而不增加 PPARγ 结合活性。另一种 L 型钙通道阻滞剂氨氯地平（amlodipine）和钙螯合剂 1,2-双-（邻-氨基苯氧基）乙烷-N,N,N',N'-四乙酸四乙酸甲酯（BAPTA-AM）降低了 PPARγ 的活性，表明硝苯地平并非通过钙通道阻滞剂活性激活 PPARγ。细胞外信号调节激酶 1/2 的失活抑制了 PPARγ2-Ser112 的磷酸化并诱导了 PPARγ 的激活。硝苯地平抑制细胞外信号调节激酶 1/2 的激活和 PPARγ2-Ser112 的磷酸化，并且将 PPARγ2-Ser112 突变为 Ala 则消除了硝苯地平介导的 PPARγ 激活。这些结果表明硝苯地平抑制细胞外信号调节激酶 1/2 的活性和 PPARγ2-Ser112 的磷酸化，从而导致 PPARγ 的激活。硝苯地平抑制脂多糖诱导的单核细胞趋化蛋白-1 的表达并诱导 ATP 结合盒转运体 A1mRNA 的表达，而针对 PPARγ 的小干扰 RNA 则消除了这些作用。此外，在载脂蛋白 E 缺陷小鼠中，硝苯地平治疗降低了动脉粥样硬化病变的大小，降低了 PPARγ2-Ser112 和细胞外信号调节激酶 1/2 的磷酸化，以及单核细胞趋化蛋白-1 mRNA 的表达并增加了主动脉中的 ATP 结合盒转运体 A1 的表达。
与氨氯地平不同，硝苯地平抑制 PPARγ-Ser 磷酸化并激活 PPARγ，以抑制巨噬细胞中单核细胞趋化蛋白-1 的表达并诱导 ATP 结合盒转运体 A1 的表达。这些作用可能在高血压患者中诱导抗动脉粥样硬化作用。
