Dept. of Internal Medicine (K.G., E.A.A., E.R.-B., I.M.V.d.B.-G., A.M., R.d.V., A.H.J.D., A.J.M.R.), Dept. of Molecular Genetics (I.v.d.P., R.B.), Dept. of Vascular Surgery (I.v.d.P.), Erasmus Medical Center, Rotterdam, The Netherlands, and Intra-Cellular Therapies, Inc., New York, New York (S.D., W.Y., G.L.S., R.E.D.).
Dept. of Internal Medicine (K.G., E.A.A., E.R.-B., I.M.V.d.B.-G., A.M., R.d.V., A.H.J.D., A.J.M.R.), Dept. of Molecular Genetics (I.v.d.P., R.B.), Dept. of Vascular Surgery (I.v.d.P.), Erasmus Medical Center, Rotterdam, The Netherlands, and Intra-Cellular Therapies, Inc., New York, New York (S.D., W.Y., G.L.S., R.E.D.)
J Pharmacol Exp Ther. 2021 Aug;378(2):173-183. doi: 10.1124/jpet.121.000628. Epub 2021 Jun 7.
Diminished nitric oxide-cGMP-mediated relaxation plays a crucial role in cardiovascular aging, leading to decreased vasodilation, vascular hypertrophy and stiffening, and ultimately, cardiovascular dysfunction. Aging is the time-related worsening of physiologic function due to complex cellular and molecular interactions, and it is at least partly driven by DNA damage. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice provides us an efficient tool to accelerate vascular aging, explore mechanisms, and test potential treatments. Previously, we identified the cGMP-degrading enzyme phosphodiesterase 1 as a potential treatment target in vascular aging. In the present study, we studied the effect of acute and chronic treatment with ITI-214, a selective phosphodiesterase 1 inhibitor on vascular aging features in mice. Compared with wild-type mice, mice at the age of 14 weeks showed decreased reactive hyperemia, diminished endothelium-dependent and -independent responses of arteries in organ baths, carotid wall hypertrophy, and elevated circulating levels of inflammatory cytokines. Acute ITI-214 treatment in organ baths restored the arterial endothelium-independent vasodilation in mice. An 8-week treatment with 100 mg/kg per day ITI-214 improved endothelium-independent relaxation in both aorta and coronary arteries, at least partly restored the diminished reactive hyperemia, lowered the systolic and diastolic blood pressure, normalized the carotid hypertrophy, and ameliorated inflammatory responses exclusively in mice. These findings suggest phosphodiesterase 1 inhibition would provide a powerful tool for nitric oxide-cGMP augmentation and have significant therapeutic potential to battle arteriopathy related to aging. SIGNIFICANCE STATEMENT: The findings implicate the key role of phosphodiesterase 1 in vascular function and might be of clinical importance for the prevention of mortalities and morbidities related to vascular complications during aging, as well as for patients with progeria that show a high risk of cardiovascular disease.
一氧化氮-cGMP 介导的舒张功能减弱在心血管衰老中起着关键作用，导致血管舒张功能下降、血管肥厚和僵硬，最终导致心血管功能障碍。衰老是由于复杂的细胞和分子相互作用导致的生理功能随时间恶化，至少部分是由 DNA 损伤驱动的。在小鼠中敲除 DNA 修复酶 ERCC1 内切酶的基因缺失为我们提供了加速血管衰老、探索机制和测试潜在治疗方法的有效工具。之前，我们确定 cGMP 降解酶磷酸二酯酶 1 是血管衰老的潜在治疗靶点。在本研究中，我们研究了选择性磷酸二酯酶 1 抑制剂 ITI-214 对 14 周龄小鼠血管衰老特征的急性和慢性作用。与野生型小鼠相比，14 周龄的 小鼠表现出反应性充血减少、器官浴中动脉内皮依赖性和非依赖性反应减弱、颈动脉壁肥厚和循环中炎症细胞因子水平升高。在器官浴中急性给予 ITI-214 可恢复 小鼠的动脉非内皮依赖性血管舒张。每天 100mg/kg 的 ITI-214 治疗 8 周可改善主动脉和冠状动脉的非内皮依赖性舒张，至少部分恢复了减弱的反应性充血，降低了收缩压和舒张压，使颈动脉肥大正常化，并仅在 小鼠中改善了炎症反应。这些发现表明，磷酸二酯酶 1 抑制可能为一氧化氮-cGMP 增强提供强大工具，并具有显著的治疗潜力，可对抗与衰老相关的动脉病变。意义陈述：这些发现表明磷酸二酯酶 1 在血管功能中的关键作用，对于预防衰老过程中与血管并发症相关的死亡率和发病率，以及对于具有心血管疾病高风险的早衰患者具有重要的临床意义。
