Department of Cardiology, Peking University People’s Hospital, No. 11 Xizhimen South St, Xicheng District, Beijing 100044, China.
J Cardiovasc Pharmacol. 2011 Feb;57(2):213-22. doi: 10.1097/FJC.0b013e31820376ac.
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), which is produced primarily by macrophages and is predominately found in the blood and in atherosclerotic plaques, represents a potentially promising target for combating atherosclerosis. Although statins are known to decrease the levels and activity of circulating and plaque Lp-PLA(2) during atherosclerosis, little is known regarding the mechanisms underlying inhibition of Lp-PLA(2) by statins. Therefore, the aim of this study was to explore the molecular mechanisms responsible for inhibition of Lp-PLA(2) by statins. Our results showed that treatment with simvastatin inhibited lipopolysaccharide (LPS)-induced increases in Lp-PLA(2) expression and secreted activity in human monocyte–derived macrophages in a dose- and time-dependent manner. These effects could be reversed by treatment with mevalonate or geranylgeranyl pyrophosphate (GGPP), but not by treatment with squalene or farnesyl pyrophosphate. Treatment with the Rho inhibitor C3 exoenzyme also inhibited LPS-induced increases in Lp-PLA(2) expression and secreted activity, mimicking the effects of simvastatin. In addition, treatment with simvastatin blocked LPS-induced activation of RhoA, which could be abolished by treatment with GGPP. Inhibition of p38 mitogen-activated protein kinase (MAPK), but not extracellular signal regulated kinase 1/2 or Jun N-terminal kinase, suppressed LPS-induced increases in Lp-PLA(2) expression and secreted activity, similar to the effects of simvastatin. Treatment of human monocyte–derived macrophages with either simvastatin or C3 exoenzyme prevented LPS-induced activation of p38 MAPK, which could be abolished by treatment with GGPP. Together, these results suggest that simvastatin reduces Lp-PLA(2) expression and secreted activity in LPS-stimulated human monocyte–derived macrophages through the inhibition of the mevalonate–GGPP–RhoA-p38 MAPK pathway. These observations provide novel evidence that statins have pleiotropic effects and suggest that inhibition of Lp-PLA(2) via this mechanism may account, at least in part, for the clinical benefit of statins in combating atherosclerosis.
脂蛋白相关磷脂酶 A(2)（Lp-PLA(2)）主要由巨噬细胞产生，主要存在于血液和动脉粥样硬化斑块中，是一种有潜力的抗动脉粥样硬化治疗靶点。尽管他汀类药物已知可降低动脉粥样硬化过程中循环和斑块 Lp-PLA(2)的水平和活性，但关于他汀类药物抑制 Lp-PLA(2)的机制知之甚少。因此，本研究旨在探讨他汀类药物抑制 Lp-PLA(2)的分子机制。我们的研究结果表明，辛伐他汀可剂量依赖性和时间依赖性地抑制脂多糖（LPS）诱导的人单核细胞衍生巨噬细胞中 Lp-PLA(2)表达和分泌活性的增加。这些作用可被甲羟戊酸或香叶基香叶基焦磷酸（GGPP）逆转，但不能被角鲨烯或法呢基焦磷酸逆转。用 Rho 抑制剂 C3 外切酶处理也可抑制 LPS 诱导的 Lp-PLA(2)表达和分泌活性的增加，类似于辛伐他汀的作用。此外，辛伐他汀抑制 LPS 诱导的 RhoA 激活，该作用可被 GGPP 逆转。抑制 p38 丝裂原活化蛋白激酶（MAPK），而不是细胞外信号调节激酶 1/2 或 Jun N-末端激酶，可抑制 LPS 诱导的 Lp-PLA(2)表达和分泌活性的增加，类似于辛伐他汀的作用。用辛伐他汀或 C3 外切酶处理人单核细胞衍生巨噬细胞可防止 LPS 诱导的 p38 MAPK 激活，该作用可被 GGPP 逆转。总之，这些结果表明，辛伐他汀通过抑制甲羟戊酸-GGPP-RhoA-p38 MAPK 通路降低 LPS 刺激的人单核细胞衍生巨噬细胞中 Lp-PLA(2)的表达和分泌活性。这些观察结果提供了新的证据，表明他汀类药物具有多效性，并表明通过这种机制抑制 Lp-PLA(2)可能至少部分解释了他汀类药物在抗动脉粥样硬化中的临床益处。
