AMP-activated protein kinase inhibits angiotensin II-stimulated vascular smooth muscle cell proliferation
AMP-activated protein kinase inhibits angiotensin II-stimulated vascular smooth muscle cell proliferation
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DOI：
10.1161/01.cir.0000136025.96811.76
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发表时间：
2004-07-27
期刊：
影响因子：
37.8
通讯作者：
Hirata, Y
中科院分区：
文献类型：
--
作者：
Nagata, D;Takeda, R;Hirata, Y
背景 AMP 激活蛋白激酶 ( AMPK) 是一种应激激活蛋白激酶，可作为细胞 ATP 水平的代谢传感器。在此，我们研究了 AMPK 信号传导是否在调节大鼠血管平滑肌细胞 (VSMC) 中血管紧张素 II (Ang II) 诱导的增殖信号中发挥作用。方法和结果-氨基咪唑-4-甲酰胺-1-β-呋喃核苷 (AICAR) 激活大鼠 VSMC 中的 AMPK，并抑制 Ang II 诱导的细胞外信号调节激酶 1/2 磷酸化，但不抑制 p38 MAPK 或 p38 MAPK 的磷酸化。 Akt/PKB。尽管 Ang II 激活 AMPK，但过氧化氢酶、N-乙酰半胱氨酸和氯化二亚苯基碘鎓（一种 NADPH 氧化酶抑制剂）显着抑制这种激活。此外，AMPK 被 H2O2 激活的观察表明 AMPK 是氧化还原敏感的。 Ang II 1 型受体拮抗剂缬沙坦而非 Ang II 2 型受体拮抗剂 PD123319 显着抑制 Ang II 诱导的 AMPK 激活，表明 Ang II 诱导的 AMPK 激活是 Ang II 1 型受体依赖性的。当用 1 mmol/L AICAR 预处理细胞时，用 Ang II 处理的 VSMC 的 H-3-胸苷掺入显着受到抑制，而显性失活 AMPK 过表达对 AMPK 的抑制增强了 Ang II 诱导的细胞增殖。皮下注射 AICAR（每天 1 mg/g 体重）两周，可抑制大鼠股动脉腔内机械损伤后的新内膜形成。结论 - 我们的研究结果表明，Ang II 诱导的 AMPK 激活与细胞外信号调节激酶信号传导同步，并且 AMPK 作为 Ang II 增殖途径的抑制剂。 AMPK 信号传导可能成为心血管疾病血管重塑的新治疗靶点。
Background-AMP-activated protein kinase ( AMPK) is a stress-activated protein kinase that works as a metabolic sensor of cellular ATP levels. Here, we investigated whether AMPK signaling has a role in the regulation of the angiotensin II (Ang II)-induced proliferation signal in rat vascular smooth muscle cells (VSMCs).Methods and Results-Aminoimidazole-4-carboxamide-1-beta-ribofuranoside (AICAR) activated AMPK in rat VSMCs and inhibited Ang II-induced extracellular signal-regulated kinase 1/2 phosphorylation but not that of p38 MAPK or Akt/PKB. Although Ang II activated AMPK, this activation was significantly inhibited by catalase, N-acetylcysteine, and diphenyleneiodonium chloride, an NADPH oxidase inhibitor. Moreover, the observation that AMPK was activated by H2O2 suggests that AMPK is redox sensitive. The Ang II type 1 receptor antagonist valsartan but not the Ang II type 2 receptor antagonist PD123319 significantly inhibited Ang II-induced AMPK activation, suggesting that Ang II-induced AMPK activation was Ang II type 1 receptor dependent. Whereas H-3-thymidine incorporation by VSMCs treated with Ang II was significantly inhibited when the cells were pretreated with 1 mmol/L AICAR, the inhibition of AMPK by dominant-negative AMPK overexpression augmented Ang II-induced cell proliferation. Subcutaneous injection of AICAR (1 mg/g body weight per day) for 2 weeks suppressed neointimal formation after transluminal mechanical injury of the rat femoral artery.Conclusions-Our findings indicate that Ang II-induced AMPK activation is synchronized with extracellular signal-regulated kinase signaling and that AMPK works as an inhibitor of the Ang II proliferative pathway. AMPK signaling might serve as a new therapeutic target of vascular remodeling in cardiovascular diseases.