Abdominal aortic aneurysm (AAA) is characterized by aorta dilation due to wall degeneration, which mostly occurs in elderly males. Vascular aging is implicated in degenerative vascular pathologies, including AAA. Cyclic nucleotide phosphodiesterases, by hydrolyzing cyclic nucleotides, play critical roles in regulating vascular structure remodeling and function. Cyclic nucleotide phosphodiesterase 1C (PDE1C) expression is induced in dedifferentiated and aging vascular smooth muscle cells (SMCs), while little is known about the role of PDE1C in aneurysm. We observed that PDE1C was not expressed in normal aorta but highly induced in SMC-like cells in human and murine AAA. In mouse AAA models induced by Angiotensin II or periaortic elastase, PDE1C deficiency significantly decreased AAA incidence, aortic dilation, and elastin degradation, which supported a causative role of PDE1C in AAA development in vivo. Pharmacological inhibition of PDE1C also significantly suppressed preestablished AAA. We showed that PDE1C depletion antagonized SMC senescence in vitro and/or in vivo, as assessed by multiple senescence biomarkers, including senescence-associated β-galactosidase activity, γ-H2AX foci number, and p21 protein level. Interestingly, the role of PDE1C in SMC senescence in vitro and in vivo was dependent on Sirtuin 1 (SIRT1). Mechanistic studies further showed that cAMP derived from PDE1C inhibition stimulated SIRT1 activation, likely through a direct interaction between cAMP and SIRT1, which leads to subsequent up-regulation of SIRT1 expression. Our findings provide evidence that PDE1C elevation links SMC senescence to AAA development in both experimental animal models and human AAA, suggesting therapeutical significance of PDE1C as a potential target against aortic aneurysms.

腹主动脉瘤 (AAA) 的特征是由于管壁退化导致的主动脉扩张，这主要发生在老年男性中。血管老化与退行性血管病变有关，包括 AAA。环核苷酸磷酸二酯酶通过水解环核苷酸，在调节血管结构重塑和功能方面发挥关键作用。在去分化和老化的血管平滑肌细胞 (SMC) 中诱导环核苷酸磷酸二酯酶 1C (PDE1C) 表达，而关于 PDE1C 在动脉瘤中的作用知之甚少。我们观察到 PDE1C 在正常主动脉中不表达，但在人和鼠 AAA 的 SMC 样细胞中高度诱导。在血管紧张素 II 或主动脉周围弹性蛋白酶诱导的小鼠 AAA 模型中，PDE1C 缺乏显着降低 AAA 发生率、主动脉扩张和弹性蛋白降解，这支持了 PDE1C 在体内 AAA 发展中的致病作用。PDE1C 的药理抑制作用也显着抑制了预先建立的 AAA。我们发现 PDE1C 耗竭在体外和/或体内拮抗 SMC 衰老，这是通过多种衰老生物标志物评估的，包括衰老相关的 β-半乳糖苷酶活性、γ-H2AX 病灶数和 p21 蛋白水平。有趣的是，PDE1C 在体外和体内 SMC 衰老中的作用取决于 Sirtuin 1 (SIRT1)。机制研究进一步表明，源自 PDE1C 抑制的 cAMP 刺激了 SIRT1 的激活，可能是通过 cAMP 和 SIRT1 之间的直接相互作用，从而导致随后的 SIRT1 表达上调。