Rosuvastatin Attenuates Ang II-Mediated Cardiomyocyte Hypertrophy via Inhibition of LOX-1
Rosuvastatin Attenuates Ang II-Mediated Cardiomyocyte Hypertrophy via Inhibition of LOX-1
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DOI：
10.1177/1074248409344329
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发表时间：
2009-12-01
影响因子：
2.6
通讯作者：
Mehta, Jawahar L.
中科院分区：
文献类型：
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作者：
Kang, Bum-Yong;Mehta, Jawahar L.
3-羟基-3-甲基戊二酰辅酶A (HMG-CoA) 还原酶抑制剂，也称为他汀类药物，已被证明可以减少心脏重塑。血管紧张素 II (Ang II) 1 型受体 (AT1R) 和氧化低密度脂蛋白 (ox-LDL) 通过其凝集素样 ox-LDL 受体 (LOX-1) 是心肌细胞生长的主要刺激物。我们推测瑞舒伐他汀是一种有效的 HMG-CoA 还原酶抑制剂，可能通过抑制 AT1R 和 LOX-1 来减少 Ang II 介导的心肌细胞生长。将 HL-1 成年小鼠心肌细胞在无血清培养基中孵育过夜，然后用瑞舒伐他汀、AT1R 抑制剂氯沙坦或抗 LOX-1 抗体处理 3 小时。然后用Ang II 刺激细胞。我们使用逆转录聚合酶链式反应 (RT-PCR) 和实时定量 PCR 测量了心肌细胞生长以及相关的细胞内氧化还原信号。氯沙坦和抗 LOX-1 抗体显着减弱 Ang II 介导的氧化应激，以及烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶（p40(phox) 和 gp91(phox) 亚基）和核因子 -kappa B (NF-kappa B) 的表达。 Rosuvastatin 可减弱 Ang II 介导的 NAPDH 氧化酶和 NF-kappa B 两个亚基的上调。Rosuvastatin 还可减少 Ang II 介导的 AT1R 和 LOX-1 的上调。在其他实验中，通过pCI-neo/LOX-1转染，心肌细胞中LOX-1上调，这也增强了AT1R信使RNA（mRNA）的表达，而瑞舒伐他汀预处理降低了该系统中LOX-1和AT1R的表达。因此，瑞舒伐他汀通过抑制 LOX-1 和 AT1R 表达并抑制细胞内氧化还原状态增强来减弱 Ang II 介导的心肌细胞生长。
3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, also known as statins, have been shown to reduce cardiac remodeling. Angiotensin II (Ang II) type 1 receptor (AT1R) and oxidized low-density lipoprotein (ox-LDL) via its lectin-like ox-LDL receptor (LOX-1) are major stimuli for cardiomyocyte growth. We postulated that rosuvastatin, a potent HMG-CoA reductase inhibitor, may reduce Ang II-mediated cardiomyocyte growth via AT1R and LOX-1 inhibition. HL-1 adult mouse cardiomyocytes were incubated overnight in serum-free medium, and then treated with rosuvastatin, the AT1R inhibitor losartan or anti-LOX-1 antibody for 3 hours. The cells were then stimulated with Ang II. We measured cardiomyocyte growth, and associated intracellular redox signals using reverse transcription-polymerase chain reaction (RT-PCR) and real-time quantitative PCR. Losartan and anti-LOX-1 antibody markedly attenuated Ang II-mediated oxidant stress, and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p40(phox) and gp91(phox) subunits) and nuclear factor-kappa B (NF-kappa B). Rosuvastatin attenuated the Ang II-mediated upregulation of both subunits of NAPDH oxidase as well as NF-kappa B. Rosuvastatin also reduced Ang II-mediated upregulation of AT1R and LOX-1. In other experiments, LOX-1 was upregulated in cardiomyocytes by transfection with pCI-neo/LOX-1, which also enhanced the expression AT1R messenger RNA (mRNA), and rosuvastatin pretreatment reduced the expression of both LOX-1 and AT1R in this system. Thus, rosuvastatin attenuates Ang II-mediated cardiomyocyte growth by inhibiting LOX-1 and AT1R expression and suppressing the heightened intracellular redox state.