Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm.
Chongyang ZhangHongmei ZhaoYujun CaiJian XiongAmy MohanDanfei LouHangchuan ShiYishuai ZhangXiaochun LongJiangning LiuChen YanPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.
Keyphrases
- endothelial cells
- abdominal aortic aneurysm
- angiotensin ii
- vascular smooth muscle cells
- high glucose
- dna damage
- aortic valve
- poor prognosis
- binding protein
- ischemia reperfusion injury
- left ventricular
- stress induced
- heart failure
- risk factors
- smoking cessation
- climate change
- small molecule
- induced pluripotent stem cells
- protein protein
- protein kinase
- long non coding rna