Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
Mol Med Rep. 2017 Oct;16(4):4545-4552. doi: 10.3892/mmr.2017.7211. Epub 2017 Aug 10.
Previous studies have demonstrated that lercanidipine, a calcium channel blocker, may protect against cardiac hypertrophy; however, the underlying mechanisms remain unclear. In the present study, the effects of lercanidipine on hypertrophy and the mechanisms involved were investigated. Cardiomyocytes isolated from neonatal rats were cultured and treated with angiotensin II (Ang II) in the presence or absence of lercanidipine or tacrolimus (FK506, a calcineurin inhibitor). Reverse transcription‑quantitative polymerase chain reaction was used to assess the mRNA expression of genes of interest, whereas the protein expression of calcium‑dependent signaling molecules was detected using western blot analysis. In addition, the cell surface area and the nuclear translocation of target proteins were evaluated using immunofluorescence. The results of the present study demonstrated that lercanidipine and FK506 inhibited Ang II‑induced cardiomyocyte hypertrophy, as evidenced by decreases in fetal gene (atrial natriuretic peptide and brain natriuretic peptide) expression levels and cell surface area. Notably, lercanidipine suppressed Ang II‑induced activation of calcineurin A (CnA) and nuclear factor of activated T cells 3 (NFAT3). In addition, calcium/calmodulin‑dependent kinase II (CaMKII)‑histone deacetylase 4 (HDAC4) signaling was also inhibited by lercanidipine. In conclusion, the present study demonstrated that lercanidipine may ameliorate cardiomyocyte hypertrophy, possibly partially by blocking Cn-NFAT3 and CaMKII-HDAC4 signaling.
先前的研究表明，钙通道阻滞剂乐卡地平可能对心肌肥厚具有保护作用；然而，其潜在机制尚不清楚。在本研究中，研究了乐卡地平对心肌肥厚的影响及其涉及的机制。分离新生大鼠的心肌细胞，并在存在或不存在乐卡地平或他克莫司（FK506，钙调神经磷酸酶抑制剂）的情况下用血管紧张素 II（Ang II）进行处理。采用逆转录-定量聚合酶链反应来评估感兴趣基因的 mRNA 表达，而使用蛋白质印迹分析检测钙依赖性信号分子的蛋白表达。此外，还通过免疫荧光法评估细胞表面积和靶蛋白的核易位。本研究的结果表明，乐卡地平和 FK506 抑制 Ang II 诱导的心肌细胞肥大，表现为胎基因（心钠肽和脑钠肽）表达水平和细胞表面积降低。值得注意的是，乐卡地平抑制了 Ang II 诱导的钙调神经磷酸酶 A（CnA）和激活 T 细胞核因子 3（NFAT3）的激活。此外，乐卡地平还抑制钙/钙调蛋白依赖性激酶 II（CaMKII）-组蛋白去乙酰化酶 4（HDAC4）信号。综上所述，本研究表明，乐卡地平可能改善心肌细胞肥大，其机制可能部分通过阻断 Cn-NFAT3 和 CaMKII-HDAC4 信号。
