Division of Pharmacology, University of Antwerp, Antwerp, Belgium.
J Cardiovasc Pharmacol. 2010 Mar;55(3):269-75. doi: 10.1097/FJC.0b013e3181d0bec3.
Because macrophages play an important role in the destabilization of atherosclerotic plaques, and smooth muscle cells (SMCs) contribute to plaque stability, selective clearance of macrophages in atherosclerotic plaques is a promising strategy for plaque stabilization. In the present study, we investigated the effects of fluvastatin, simvastatin, lovastatin, and pravastatin on the viability of macrophages and SMCs. All statins, except pravastatin, induced cell death of J774A.1 macrophages after 24 hours, albeit with different sensitivity. The viability of rabbit aortic SMCs was hardly affected. Fluvastatin-induced macrophage cell death was characterized as apoptosis and could be reversed by isoprenoid intermediates of the mevalonate pathway. Peritoneal macrophages from male or female mice were much more resistant to statin-induced cell death. The high sensitivity of J774A.1 macrophages to statin-induced cell death was related to the strong 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in these cells. Macrophage and SMC content of rabbit atherosclerotic plaques was not affected after in vitro treatment with fluvastatin or lovastatin for 3 days. In conclusion, fluvastatin, simvastatin, and lovastatin, but not pravastatin, can selectively induce apoptosis in J774A.1 macrophages, but not in SMCs, primary macrophages or rabbit atherosclerotic plaques. This effect was related to the degree of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in the different cell types.
由于巨噬细胞在动脉粥样硬化斑块的不稳定中发挥重要作用，而平滑肌细胞（SMC）有助于斑块稳定，因此选择性清除动脉粥样硬化斑块中的巨噬细胞是稳定斑块的一种有前途的策略。在本研究中，我们研究了氟伐他汀、辛伐他汀、洛伐他汀和普伐他汀对巨噬细胞和 SMC 活力的影响。除普伐他汀外，所有他汀类药物在 24 小时后均诱导 J774A.1 巨噬细胞死亡，但敏感性不同。兔主动脉 SMC 的活力几乎不受影响。氟伐他汀诱导的巨噬细胞死亡表现为细胞凋亡，并可被甲羟戊酸途径的异戊烯基中间体逆转。来自雄性或雌性小鼠的腹腔巨噬细胞对他汀类药物诱导的细胞死亡的抵抗力要强得多。J774A.1 巨噬细胞对他汀类药物诱导的细胞死亡的高敏感性与其细胞中强的 3-羟-3-甲基戊二酰基辅酶 A 还原酶活性有关。在体外用氟伐他汀或洛伐他汀处理 3 天后，兔动脉粥样硬化斑块中的巨噬细胞和 SMC 含量没有受到影响。总之，氟伐他汀、辛伐他汀和洛伐他汀但不是普伐他汀可以选择性地诱导 J774A.1 巨噬细胞凋亡，但不诱导 SMC、原代巨噬细胞或兔动脉粥样硬化斑块凋亡。这种作用与不同细胞类型中 3-羟-3-甲基戊二酰基辅酶 A 还原酶活性的程度有关。
