Small-molecule inhibitors of signal transducer and activator of transcription 3 protect against angiotensin II-induced vascular dysfunction and hypertension.
Small-molecule inhibitors of signal transducer and activator of transcription 3 protect against angiotensin II-induced vascular dysfunction and hypertension.
复制标题
DOI：
10.1161/hypertensionaha.111.00299
复制
发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Faraci FM
中科院分区：
文献类型：
--
作者：
Johnson AW;Kinzenbaw DA;Modrick ML;Faraci FM
已知血管紧张素II(Ang II)可促进血管疾病和高血压，部分原因是通过形成细胞因子，如白介素6(IL-6)。然而，信号转导和转录激活因子3(STAT3)在这些过程中的作用以及Ang II/IL-6信号转导机制尚不清楚。使用两个模型，我们检验了STAT3在血管紧张素转换酶II诱导的血管功能障碍和高血压中起重要作用的假设。C57BL/6J小鼠的分离颈动脉与血管紧张素转换酶II孵育一夜后，血管内皮细胞依赖性激动剂乙酰胆碱(Ach)对血管扩张的反应比对照组增加了~2倍，血管扩张反应降低了约50%(P<；0.05)。这些作用可通过添加STAT3激活的小分子抑制剂(S3I-201或STATTIC)来阻止。在体内，注射血管紧张素II(1.4mgkg−1day−1)的小鼠在第14天时，动脉压比赋形剂处理的小鼠增加了约40毫米汞柱，这种作用可被S3I-201治疗(5 mg kg−1ip，q.o.d)所阻止。全身应用血管紧张素转换酶II后，颈动脉和基底动脉对乙酰胆碱的扩张性反应降低约30-50%，而S3I-201治疗可阻止大部分这种损害(P<；0.05)。与对血管功能和血压的影响相反，S31-201不能阻止Ang II诱导的颈动脉肥厚。这些发现首次证明了STAT3激活抑制剂对血管紧张素转换酶II诱导的氧化应激、内皮功能障碍和高血压有保护作用。由于Ang II在多种心血管危险因素存在的情况下促进血管疾病，这些结果表明选择性靶向STAT3可能具有实质性的治疗潜力。
Angiotensin II (Ang II) is known to promote vascular disease and hypertension in part by formation of cytokines like interleukin-6 (IL-6). However, the role of signal transducer and activator of transcription 3 (STAT3) in these process and Ang II/IL-6 signaling is unclear. Using two models, we tested the hypothesis that STAT3 is essential for Ang II-induced vascular dysfunction and hypertension. Incubation of isolated carotid arteries from C57BL/6J mice with Ang II overnight increased superoxide ~2 fold and reduced vasodilator responses to the endothelium-dependent agonist acetylcholine (Ach) by ~50% vs controls (P<0.05). These effects were prevented by the addition of small molecular inhibitors of STAT3 activation (S3I-201 or STATTIC). In vivo, administration of Ang II (1.4 mg kg−1 day−1) using osmotic minipumps increased arterial pressure by ~40 mmHg at day 14 compared to vehicle treated mice and this effect was prevented by S3I-201 treatment (5 mg kg−1 IP, q.o.d.). Following systemic treatment with Ang II, dilator responses to acetylcholine were reduced by ~30-50% in carotid artery and basilar arteries whereas S3I-201 treatment prevented most of this impairment (P<0.05). In contrast to effects on vascular function and blood pressure, S31-201 did not prevent Ang II-induced hypertrophy in the carotid artery. These findings provide the first evidence that inhibitors of STAT3 activation protect against Ang II-induced oxidative stress, endothelial dysfunction, and hypertension. Because Ang II promotes vascular disease in the presence of multiple cardiovascular risk factors, these results suggest selective targeting STAT3 may have substantial therapeutic potential.