BACKGROUND:Ssmall-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 reverse siRNA silencing, RVR technology is a potential approach to counteract siRNA effects.METHODS: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.RESULTS: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.CONCLUSIONS: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.

中文翻译：

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用 REVERSIR 抵消血管紧张素原小干扰 RNA 介导的抗高血压作用

背景：靶向肝脏 AGT（血管紧张素原）mRNA 的小干扰 RNA (siRNA) 可消耗 AGT，从而降低血压长达 6 个月。然而，某些情况可能需要快速增加血管紧张素。反向siRNA沉默RVR技术是抵消siRNA效应的潜在方法。方法：自发性高血压大鼠接受10 mg/kg AGT siRNA，3周后给予AGT-RVR（1、10或20 mg/kg）。 AGT-RVR 给药一周后，重新给药 AGT siRNA 评估其 AGT-RVR 后两周的有效性。此外，还检查了等压剂量的缬沙坦（每天 4 mg/kg）后 AGT-RVR 的影响。 结果：基线平均动脉压 (MAP) 为 144±1 mm Hg。 AGT siRNA 使 MAP 降低约 16 mm Hg，使 AGT 降低 >95%，而肾素则增加 25 倍。所有 AGT-RVR 剂量均在 4 至 7 天内将 MAP 恢复至基线。值得注意的是，10 和 20 mg/kg 使 AGT 和肾素恢复至基线，而 1 mg/kg 则使 AGT 恢复约 50%，且肾素仍高于基线。在 1 mg/kg AGT-RVR 后进行第二次 AGT siRNA 治疗，将 MAP 降低至与初始剂量相同的程度，而在 10 mg/kg AGT-RVR 后，其产生的 MAP 效果约为第一个剂量 MAP 效果的 50%。 2周。缬沙坦诱导的 MAP 降低不受 AGT-RVR 的影响。结论：在自发性高血压大鼠中，血管紧张素原-RVR 剂量依赖性地逆转 AGT siRNA 诱导的 AGT 降低，使 MAP 正常化。即使 AGT 水平恢复了 50%，MAP 仍持续正常化，这可能是由于肾素上调维持了足够的血管紧张素生成。 AGT-RVR 给药后，第二剂 AGT siRNA 再次降低 MAP。