Ogino Atsushi, Takemura Genzou, Kanamori Hiromitsu, Okada Hideshi, Maruyama Rumi, Miyata Shusaku, Esaki Masayasu, Nakagawa Munehiro, Aoyama Takuma, Ushikoshi Hiroaki, Kawasaki Masanori, Minatoguchi Shinya, Fujiwara Takako, Fujiwara Hisayoshi
Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2271-80. doi: 10.1152/ajpheart.00303.2007. Epub 2007 Jul 20.
Although amlodipine, a long-acting L-type calcium channel blocker, reportedly prevents left ventricular remodeling and dysfunction after myocardial infarction, the mechanism responsible is not yet well understood. Myocardial infarction was induced in mice by ligating the left coronary artery. Treatment of mice with amlodipine (10 mg x kg(-1) x day(-1)), beginning on the third day postinfarction, significantly improved survival and attenuated left ventricular dilatation and dysfunction 4 wk postinfarction compared with treatment with saline or hydralazine. Although infarct sizes did not differ among the groups, the infarcted wall thickness was greater and the infarct segment length was smaller in the amlodipine-treated group, and cellular components, including vessels and myofibroblasts, were abundant within the infarcted area. Ten days postinfarction (the subacute stage), the proliferation of granulation tissue cells in the infarcted area was similar among the groups, but the incidence of apoptosis was significantly lower in the amlodipine-treated group, where Bad, a proapoptotic Bcl-2 family protein, was significantly phosphorylated (inactivated). Calcineurin, which dephosphorylates (activates) Bad, was upregulated in infarcted hearts, but its levels were significantly reduced by amlodipine treatment. In vitro, Fas stimulation augmented calcineurin activity and induced apoptosis among infarct tissue-derived myofibroblasts; both of those effects were strongly inhibited by amlodipine, two other calcium channel blockers (verapamil or nifedipine), and two calcineurin inhibitors (cyclosporin A or FK-506). Amlodipine inhibits Fas-mediated granulation tissue cell apoptosis in infarcted hearts, possibly by attenuating the activities of calcineurin and Bad. These findings may provide new insight into the mechanism by which calcium channel blockers attenuate postinfarction cardiac remodeling and dysfunction.
尽管长效L型钙通道阻滞剂氨氯地平据报道可预防心肌梗死后的左心室重构和功能障碍，但其作用机制尚未完全明确。通过结扎左冠状动脉在小鼠中诱导心肌梗死。在心肌梗死后第三天开始用氨氯地平（10 mg·kg⁻¹·d⁻¹）治疗小鼠，与用生理盐水或肼屈嗪治疗相比，显著提高了生存率，并减轻了心肌梗死后4周的左心室扩张和功能障碍。尽管各组梗死面积无差异，但氨氯地平治疗组的梗死壁厚度更大，梗死节段长度更小，梗死区域内包括血管和成肌纤维细胞在内的细胞成分丰富。心肌梗死后10天（亚急性期），各组梗死区域肉芽组织细胞的增殖相似，但氨氯地平治疗组的凋亡发生率显著降低，其中促凋亡Bcl-2家族蛋白Bad被显著磷酸化（失活）。使Bad去磷酸化（激活）的钙调神经磷酸酶在梗死心脏中上调，但氨氯地平治疗使其水平显著降低。在体外，Fas刺激增强了钙调神经磷酸酶活性，并诱导梗死组织来源的成肌纤维细胞凋亡；氨氯地平、另外两种钙通道阻滞剂（维拉帕米或硝苯地平）和两种钙调神经磷酸酶抑制剂（环孢素A或FK-506）均强烈抑制了这两种作用。氨氯地平可能通过减弱钙调神经磷酸酶和Bad的活性来抑制梗死心脏中Fas介导的肉芽组织细胞凋亡。这些发现可能为钙通道阻滞剂减轻心肌梗死后心脏重构和功能障碍的机制提供新的见解。
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