Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels - A potential role for serine phosphorylation in insulin/angiotensin II crosstalk
Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels - A potential role for serine phosphorylation in insulin/angiotensin II crosstalk
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DOI：
10.1172/jci119752
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发表时间：
1997-11-01
影响因子：
15.9
通讯作者：
Feener, EP
中科院分区：
文献类型：
--
作者：
Folli, F;Kahn, CR;Feener, EP
为了研究血管紧张素II（AII）和胰岛素信号系统之间的潜在相互作用，在大鼠主动脉平滑肌细胞中研究了胰岛素和AII对胰岛素受体底物1（IRS-I）磷酸化和磷脂酰肌醇（PI）3-激酶激活的调节。用AII预处理细胞可抑制胰岛素刺激的与IRS-1相关的PI 3-激酶活性达60%。虽然AII不损害胰岛素刺激的胰岛素受体（IR）P-亚基的酪氨酸磷酸化，但它使胰岛素刺激的IRS-1的酪氨酸磷酸化降低了50%。AII以剂量依赖性方式抑制胰岛素刺激的IRS-1和PI 3-激酶p85亚基之间的结合30-50%。AII对IRS-1/PI 3-激酶结合的抑制作用可被AII受体拮抗剂saralasin阻断，但不被AT、氯沙坦拮抗剂或AT（2）拮抗剂PD 123319阻断。AII增加了IR P-亚基和IRS-1的丝氨酸磷酸化。体外结合实验表明，自磷酸化使对照细胞的IR与IRS-1的结合增加了2.5倍，而AII刺激细胞的IRS-1的结合增加了1.2倍，这表明AII刺激降低了IRS-1与活化IR结合的能力。此外，AII增加了p85丝氨酸磷酸化，抑制了p85相关PI 3-激酶活性的总库，PI 3-激酶的p50/ p55调节亚基水平降低。这些结果表明，激活的肾素-血管紧张素系统可能会导致胰岛素抵抗的血管。
To investigate potential interactions between angiotensin II (AII) and the insulin signaling system in the vasculature, insulin and AII regulation of insulin receptor substrate-1 (IRS-I) phosphorylation and phosphatidylinositol (PI) 3-kinase activation were examined in rat aortic smooth muscle cells. Pretreatment of cells with AII inhibited insulin-stimulated PI 3-kinase activity associated with IRS-1 by 60%. While AII did not impair insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) P-subunit, it decreased insulin-stimulated tyrosine phosphorylation of IRS-1 by 50%. AII inhibited the insulin-stimulated association between IRS-1 and the p85 subunit of PI 3-kinase by 30-50% in a dose-dependent manner. This inhibitory effect of AII on IRS-1/PI 3-kinase association was blocked by the AII receptor antagonist saralasin, but not by AT, antagonist losartan or AT(2) antagonist PD123319. AII increased the serine phosphorylation of both the IR P-subunit and IRS-1. In vitro binding experiments showed that autophosphorylation increased IR binding to IRS-1 from control cells by 2.5-fold versus 1.2-fold for IRS-l from AII-stimulated cells, suggesting that AII stimulation reduces IRS-l's ability to associate with activated IR. In addition, AII increased p85 serine phosphorylation, inhibited the total pool of p85 associated PI 3-kinase activity, and decreased levels of the p50/ p55 regulatory subunit of PI 3-kinase. These results suggest that activation of the renin-angiotensin system may lead to insulin resistance in the vasculature.