Simultaneous Treatment with Azelnidipine and Olmesartan Inhibits Apoptosis of Hl-1 Cardiac Myocytes Expressing E334k cMyBPC
Simultaneous Treatment with Azelnidipine and Olmesartan Inhibits Apoptosis of Hl-1 Cardiac Myocytes Expressing E334k cMyBPC
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DOI：
10.1055/s-0033-1347188
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发表时间：
2013-06
期刊：
影响因子：
2.2
通讯作者：
U. Bahrudin;U. Bahrudin;N. Ikeda;S. Utami;S. Utami;Nani Maharani;Nani Maharani;K. Morikawa;Peili Li;M. A. Sobirin;A. Hasegawa;S. Sakata;R. Endo;S. Rifqi;Y. Shirayoshi;Kenshiro Yamamoto;H. Ninomiya;I. Hisatome
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文献类型：
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作者：
U. Bahrudin;U. Bahrudin;N. Ikeda;S. Utami;S. Utami;Nani Maharani;Nani Maharani;K. Morikawa;Peili Li;M. A. Sobirin;A. Hasegawa;S. Sakata;R. Endo;S. Rifqi;Y. Shirayoshi;Kenshiro Yamamoto;H. Ninomiya;I. Hisatome
背景：细胞凋亡似乎在肥厚性心肌病（HCM）的发病机制中起重要作用。我们之前报道了3例携带E334K MYBPC3的HCM患者，在培养细胞中异种表达E334K cMyBPC诱导细胞凋亡。本研究的目的是寻找能够抑制表达E334K cMyBPC的HL-1心肌细胞凋亡的药物。方法与结果：E334K cMyBPC在细胞中的表达增加了促凋亡（p53、Bax和细胞色素c）水平，降低了抗凋亡（Bcl-2和Bcl-XL）水平。β受体阻滞剂卡维地洛（1 μM）和钙通道阻滞剂贝必地尔（0.5 μM）分别使p53、Bax、细胞色素c和Bcl-XL水平正常化，而钙通道阻滞剂阿泽尼地平（1 μM）和血管紧张素受体阻滞剂奥美沙坦（10 μM）均使p53、Bax、细胞色素c和Bcl-XL水平正常化。其中细胞色素c的变化程度最大。azelnidipine （0.1 μM）和olmesartan （1 μM）分别使细胞色素c水平降低40.2±4.3%和31.3±5.1%。CCB组氨氯地平和ARB组缬沙坦分别仅降低19.1±2.1%和20.1±5.2%。流式细胞术分析和膜联蛋白V染色显示，阿泽尼地平(0.1 μM) +奥美沙坦（0.3 μM）和氨氯地平(0.1 μM) +缬沙坦（0.3 μM）分别使细胞凋亡数减少35.8±10.5%和18.4±3.2%。结论：阿泽尼地平联合奥美沙坦或氨氯地平联合缬沙坦可抑制表达E334K cMyBPC的HL-1细胞的凋亡，且前者比后者更有效。
Abstract Background: Apoptosis appears to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM). We have previously reported 3 HCM patients carrying the E334K MYBPC3, and that heterologous expression of E334K cMyBPC in cultured cells induced apoptosis. The purpose of this study was to identify pharmacological agents that would inhibit apoptosis in HL-1 cardiomyocytes expressing E334K cMyBPC. Methods and Results: E334K cMyBPC expression in cells increased levels of pro-apoptosis (p53, Bax and cytochrome c) and decreased levels of anti-apoptosis (Bcl-2 and Bcl-XL). While the beta blocker carvedilol (1 μM) normalized the level of p53 and Bcl-2 and the calcium channel blocker (CCB) bepridil (0.5 μM) normalized that of Bcl-2, both the CCB azelnidipine (1 μM) and the angiotensin receptor blocker (ARB) olmesartan (10 μM) normalized those of p53, Bax, cytochrome c, and Bcl-XL. Among those proteins, cytochrome c was the one which showed the highest degree of change. Both azelnidipine (0.1 μM) and olmesartan (1 μM) reduced the level of cytochrome c by 40.2±4.3% and 31.3±5.1%, respectively. The CCB amlodipine and the ARB valsartan reduced it only by 19.1±2.1% and 20.1±5.2%, respectively. Flow cytometric analysis and annexin V staining showed that treatment of cells with azelnidipine (0.1 μM) plus olmesartan (0.3 μM) or that with amlodipine (0.1 μM) plus valsartan (0.3 μM) reduced the number of apoptotic cells by 35.8±10.5% and 18.4±3.2%, respectively. Conclusion: Azelnidipine plus olmesartan or amlodipine plus valsartan inhibited apoptosis of HL-1 cells expressing E334K cMyBPC, and the former combination was more effective than the latter.