Small-molecule inhibitors of signal transducer and activator of transcription 3 protect against angiotensin II-induced vascular dysfunction and hypertension

Abstract

Angiotensin II (Ang II) is known to promote vascular disease and hypertension in part by formation of cytokines, such as interleukin-6. However, the role of signal transducer and activator of transcription 3 (STAT3) in these processes and Ang II/interleukin-6 signaling is unclear. Using 2 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 by ≈50% versus 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 mm Hg at day 14 compared with vehicle-treated mice, and this effect was prevented by S3I-201 treatment (5 mg/kg IP, QOD). After systemic treatment with Ang II, dilator responses to acetylcholine were reduced by ≈30% to 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 that selective targeting of STAT3 may have substantial therapeutic potential.

Figure 1

Responses of carotid arteries (n=7) to acetylcholine (A) and nitroprusside (B) following overnight incubation with vehicle or Ang II in the presence or absence of S3I-201. *P<0.001 vs vehicle at the highest concentration of acetylcholine.

Figure 2

Superoxide levels (A) in aorta treated with vehicle or Ang II in the presence or absence of S3I-201 (P<0.01, n=5). Effects of tempol (B) on responses of carotid arteries to acetylcholine following overnight treatment with vehicle or Ang II (n=5). *P<0.001 vs vehicle.

Figure 3

Effects of Ang II on arterial blood pressure (n=9)(A) and responses of the carotid artery to acetylcholine (B) following chronic infusion of Ang (1.4 mg kg⁻¹ day⁻¹) in mice treated with S3I-201 or vehicle. *P<0.05 vs vehicle.

Figure 4

Effects of Ang II on responses of basilar arteries (n=5) to acetylcholine (A), A23187 (B), and papavarine (C) following chronic infusion of Ang II (1.4 mg kg⁻¹ day⁻¹) treated with S3I-201 or vehicle. *P<0.05 vs vehicle.