TY - JOUR
T1 - Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm
AU - Zhang, Chongyang
AU - Zhao, Hongmei
AU - Cai, Yujun
AU - Xiong, Jian
AU - Mohan, Amy
AU - Lou, Danfei
AU - Shi, Hangchuan
AU - Zhang, Yishuai
AU - Long, Xiaochun
AU - Wang, Jing
AU - Yan, Chen
N1 - Funding Information:
often reported as a commonly underlying cause of senescence and lead to phosphorylation of histone H2A.XSer139, known as γ-H2AX. We found that primary cultured mouse aortic SMCs isolated from PDE1C+/+ mice revealed an intrinsically higher level of senescence compared to PDE1C−/− SMCs, as quantified by SA–β-gal–positive cell numbers over total cell numbers (Fig. 4 A and B). Overexpressing PDE1C1, a variant expressing in SMCs (12), in PDE1C−/− SMCs promoted senescence via adenovirus (Fig. 4C). Double staining of p21 and SA–β-gal activity were further performed in PDE1C+/+ and PDE1C−/− SMCs (Fig. 4D), and PDE1C−/− SMCs displayed less double-positive cells (Fig. 4E). The staining specificity was supported by negative control of p21 immunostaining (SI Appendix, Fig. S11A) and the neglectable autofluorescence of SA–β-gal staining alone (SI Appendix, Fig. S11B). Western blot (WB) further confirmed a lower level of p21 protein expression in PDE1C−/− compared to PDE1C+/+ SMCs (Fig. 4F). Additionally, γ-H2AX immunostaining (Fig. 4G and SI Appendix, Fig. S12) revealed less γ-H2AX foci number in PDE1C−/− SMC nucleus (Fig. 4H), indicating less DNA damage. Together, these results support a critical role of PDE1C in SMC senescence in vitro.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/8/3
Y1 - 2021/8/3
N2 - 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 senescenceassociated 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.
AB - 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 senescenceassociated 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.
KW - Abdominal aortic aneurysm
KW - Phosphodiesterase
KW - Senescence
KW - Vascular smooth muscle cell
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U2 - 10.1073/pnas.2107898118
DO - 10.1073/pnas.2107898118
M3 - Article
C2 - 34312235
AN - SCOPUS:85111196425
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
M1 - e2107898118
ER -