Up-regulation of Akt and eNOS induces vascular smooth muscle cell differentiation in hypertension in vivo
Up-regulation of Akt and eNOS induces vascular smooth muscle cell differentiation in hypertension in vivo
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DOI：
10.1097/01.fjc.0000157454.60939.43
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发表时间：
2005-04-01
影响因子：
3
通讯作者：
Matsuzaki, M
中科院分区：
文献类型：
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作者：
Kawahara, S;Umemoto, S;Matsuzaki, M
最近的研究表明，血管紧张素II 1型（AT 1）受体介导的Akt激活诱导血管平滑肌细胞（VSMC）的去分化。然而，影响VSMC表型的关键信号转导在体内仍不清楚。我们研究了通过AT 1受体介导的活性氧（ROS）信号转导是否可以调节易卒中的自发性高血压大鼠（SHRSPs）的VSMC表型。将雄性SHRSP随机分组，并使用载体、ACE抑制剂西拉普利或AT 1受体拮抗剂E4177治疗6周。两种药物对血压、主动脉形态和胶原沉积的影响等效。两种药物均显著降低主动脉NAD（P）H氧化酶活性和p38 MAPK及ERK表达，而p-Akt、eNOS和SM 2则显著升高。此外，E4177比西拉普利更有效地诱导VSMC分化，通过降低NAD（P）H氧化酶活性，上调p-Akt，eNOS和SM 2。因此，ACE抑制剂和AT 1受体拮抗剂通过抑制NAD（P）H氧化酶活性和上调eNOS和Akt来抑制SHRSP血管平滑肌细胞的去分化，提示与体外实验相反，AT 1受体介导的NAD（P）H氧化酶产生的ROS、eNOS和Akt可能是体内高血压VSMC表型的关键决定因素。
Recent studies have shown that angiotensin II type 1 (AT1) receptor-mediated Akt activation induces vascular smooth muscle cell (VSMC) dedifferentiation in vitro. However, the critical signal transductions affecting the VSMC phenotype remain unclear in vivo. We examined whether signal transduction through AT1 receptor-mediated reactive oxygen species (ROS) could regulate the VSMC phenotype in stroke-prone spontaneously hypertensive rats (SHRSPs). Male SHRSPs were randomized and treated for 6 weeks with a vehicle, an ACE inhibitor cilazapril, or an AT1 receptor antagonist E4177. The 2 drugs showed equipotent effects on the blood pressure, aortic morphology, and collagen deposition. Both drugs also significantly reduced aortic NAD(P)H oxidase activity and p38MAPK and ERK expression, whereas p-Akt, eNOS, and SM2 were significantly increased in SHRSP aortas. Furthermore, E4177 was more effective than cilazapril at inducing VSMC differentiation by reducing NAD(P)H oxidase activity, and up-regulating p-Akt, eNOS, and SM2. Thus, an ACE inhibitor and an AT1 receptor antagonist inhibited VSMC dedifferentiation through inhibition of NAD(P)H oxidase activity and up-regulation of eNOS and Akt in SHRSP aortas, suggesting that in contrast to the in vitro experiments, AT1 receptor-mediated NAD(P)H oxidase-generated ROS, eNOS, and Akt might be crucial determinants for the VSMC phenotype in hypertension in vivo.