Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands (D.Y., E.O.C.-L., R.v.V., I.M.G., A.H.J.D.).
Alnylam Pharmaceuticals, Cambridge, MA (A.K., K.W., H.-C.T., I.Z.).
Hypertension. 2024 Jul;81(7):1491-1499. doi: 10.1161/HYPERTENSIONAHA.124.22878. Epub 2024 May 1.
Small-interfering RNA (siRNA) targeting hepatic AGT (angiotensinogen) mRNA depletes AGT, lowering blood pressure for up to 6 months. However, certain situations may require a rapid angiotensin increase. The REVERSIR (RVR) - reverse siRNA silencing technology a potential approach to counteract siRNA effects.
Spontaneously hypertensive rats received 10 mg/kg AGT siRNA, and 3 weeks later were given AGT-RVR (1, 10, or 20 mg/kg). One week after AGT-RVR dosing, a redose of AGT siRNA assessed its post-AGT-RVR effectiveness for 2 weeks. Additionally, the impact of AGT-RVR after an equihypotensive dose of valsartan (4 mg/kg per day) was examined.
Baseline mean arterial pressure (MAP) was 144±1 mm Hg. AGT siRNA reduced MAP by ≈16 mm Hg and AGT by >95%, while renin increased 25-fold. All AGT-RVR doses restored MAP to baseline within 4 to 7 days. Notably, 10 and 20 mg/kg restored AGT and renin to baseline, while 1 mg/kg allowed ≈50% AGT restoration, with renin remaining above baseline. A second AGT siRNA treatment, following 1 mg/kg AGT-RVR, reduced MAP to the same degree as the initial dose, while following 10 mg/kg AGT-RVR, it resulted in ≈50% of the first dose's MAP effect at 2 weeks. The valsartan-induced MAP reduction was unaffected by AGT-RVR.
In spontaneously hypertensive rats, angiotensinogen-RVR dose-dependently reversed AGT siRNA-induced AGT reduction, normalizing MAP. MAP normalization persisted even with 50% recovered AGT levels, likely due to upregulated renin maintaining adequate angiotensin generation. Post-AGT-RVR dosing, a second AGT siRNA dose lowered MAP again.
靶向肝 AGT（血管紧张素原）mRNA 的小干扰 RNA（siRNA）可消耗 AGT，使血压降低长达 6 个月。然而，在某些情况下可能需要迅速增加血管紧张素。REVERSIR（RVR）-反向 siRNA 沉默技术是一种潜在的对抗 siRNA 作用的方法。
自发性高血压大鼠接受 10mg/kg AGT siRNA，3 周后给予 AGT-RVR（1、10 或 20mg/kg）。在给予 AGT-RVR 后一周，再次给予 AGT siRNA，评估其在 AGT-RVR 后的有效性 2 周。此外，还检查了 AGT-RVR 在等效降压剂量缬沙坦（4mg/kg/天）后的影响。
基线平均动脉压（MAP）为 144±1mmHg。AGT siRNA 使 MAP 降低约 16mmHg，使 AGT 降低超过 95%，同时肾素增加 25 倍。所有 AGT-RVR 剂量均在 4 至 7 天内使 MAP 恢复到基线。值得注意的是，10 和 20mg/kg 使 AGT 和肾素恢复到基线，而 1mg/kg 允许约 50%的 AGT 恢复，肾素仍高于基线。在给予 1mg/kg AGT-RVR 后，再次给予 AGT siRNA 治疗，MAP 降低的程度与初始剂量相同，而在给予 10mg/kg AGT-RVR 后，在 2 周时，MAP 降低的程度约为第一剂量的 50%。缬沙坦引起的 MAP 降低不受 AGT-RVR 的影响。
在自发性高血压大鼠中，AGT 基因-RVR 剂量依赖性地逆转了 AGT siRNA 引起的 AGT 减少，使 MAP 正常化。即使 AGT 水平恢复 50%，MAP 仍保持正常，这可能是由于肾素上调维持了足够的血管紧张素生成。在给予 AGT-RVR 后再次给予 AGT siRNA 剂量，MAP 再次降低。
