Alternative splicing of exon 24 (E24) of the myosin phosphatase regulatory subunit (Mypt1) tunes smooth muscle sensitivity to NO/cGMP-mediated vasorelaxation and thereby controls blood pressure (BP) in otherwise normal mice. This occurs via the toggling in or out of a C-terminal leucine zipper (LZ) motif required for hetero-dimerization with and activation by cGMP-dependent protein kinase cGK1α. Here we tested the hypothesis that editing (deletion) of E24, by shifting to the LZ positive isoform of Mypt1, would suppress the hypertensive response to angiotensin II (AngII). To test this, mice underwent tamoxifen-inducible and smooth muscle-specific deletion of E24 (E24 cKO) at age 6 weeks followed by a chronic slow-pressor dose of AngII (400 ng/kg/min) plus additional stressors. E24 cKO suppressed the hypertensive response to AngII alone or with the addition of a high salt diet. This effect was not a function of altered salt balance as there were no differences in intake or renal excretion of sodium. This effect was NO dependent as L-NAME in the drinking water caused an exaggerated hypertensive response in the E24cKO mice. E24cKO mouse mesenteric arteries were more sensitive to DEA/NO-induced vasorelaxation and less responsive to AngII- and α-adrenergic-induced vasoconstriction at baseline. Only the latter two effects were still present after 2 weeks of chronic AngII treatment. We conclude that editing of Mypt1 E24, by shifting the expression of naturally occurring isoforms and sensitizing to NO-mediated vasodilation, could be a novel approach to the treatment of human hypertension.

肌球蛋白磷酸酶调节亚基 (Mypt1) 的外显子 24 (E24) 的选择性剪接可调节平滑肌对 NO/cGMP 介导的血管舒张的敏感性，从而控制其他正常小鼠的血压 (BP)。这是通过切换 C 端亮氨酸拉链 (LZ) 基序而发生的，而 C 端亮氨酸拉链 (LZ) 基序是 cGMP 依赖性蛋白激酶 cGK1α 异二聚化和激活所需的。在这里，我们测试了这样的假设：通过转变为 Mypt1 的 LZ 阳性亚型，编辑（删除）E24 将抑制对血管紧张素 II (AngII) 的高血压反应。为了测试这一点，小鼠在 6 周龄时接受了他莫昔芬诱导的平滑肌特异性 E24 缺失 (E24 cKO)，随后接受慢性缓慢升压剂量的 AngII (400 ng/kg/min) 加上额外的应激源。E24 cKO 单独或添加高盐饮食可抑制对 AngII 的高血压反应。这种效应不是盐平衡改变的函数，因为钠的摄入或肾脏排泄没有差异。这种效应不依赖于饮用水中的 L-NAME，导致 E24cKO 小鼠出现过度的高血压反应。基线时，E24cKO 小鼠肠系膜动脉对 DEA/NO 诱导的血管舒张更敏感，对 AngII 和 α-肾上腺素能诱导的血管收缩反应较差。慢性 AngII 治疗 2 周后，只有后两种作用仍然存在。我们得出的结论是，通过改变天然存在的同工型的表达并对 NO 介导的血管舒张敏感来编辑 Mypt1 E24，可能是治疗人类高血压的一种新方法。