Deacetylation-dependent regulation of PARP1 by SIRT2 dictates ubiquitination of PARP1 in oxidative stress-induced vascular injury
Naijin Zhang,
Ying Zhang,
Boquan Wu,
Shaojun Wu,
Shilong You,
Saien Lu,
Jingwei Liu,
Xinyue Huang,
Jiaqi Xu,
Liu Cao,
Yingxian Sun
Affiliations
Naijin Zhang
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, 110001, Shenyang, Liaoning, PR China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, PR China
Ying Zhang
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, 110001, Shenyang, Liaoning, PR China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, PR China
Boquan Wu
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, 110001, Shenyang, Liaoning, PR China
Shaojun Wu
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, 110001, Shenyang, Liaoning, PR China
Shilong You
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, 110001, Shenyang, Liaoning, PR China
Saien Lu
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, 110001, Shenyang, Liaoning, PR China
Jingwei Liu
Key Laboratory of Medical Cell Biology, Ministry of Education, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, PR China; Institute of School of Basic Medicine, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, PR China
Xinyue Huang
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, 110001, Shenyang, Liaoning, PR China
Jiaqi Xu
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, 110001, Shenyang, Liaoning, PR China
Liu Cao
Key Laboratory of Medical Cell Biology, Ministry of Education, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, PR China; Institute of School of Basic Medicine, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, PR China; Corresponding author. Key Laboratory of Medical Cell Biology, Ministry of Education, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, PR China.
Yingxian Sun
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, 110001, Shenyang, Liaoning, PR China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, PR China; Corresponding author. Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, 110001, Shenyang, Liaoning, PR China.
Poly(ADP-ribose) polymerase 1 (PARP1) has a major regulatory role in cardiovascular disease. However, inhibiting PARP1 activity does not significantly improve clinical outcomes of cardiovascular disease, which suggests that the regulatory mechanism of PARP1 in cardiovascular disease is unclear. Here, we focused on deacetylation regulatory mechanisms of PARP1 and crosstalk of PARP1 post-translational modifications. We uncovered the crucial molecular interactions and protein modifications of deacetylase Sirtuin 2 (SIRT2) and PARP1 in vascular damage. The results showed that SIRT2 was involved in this process and oxidative stress damage factor PARP1 was a novel physiological substrate of SIRT2. SIRT2 interacted with PARP1 at the PARP-A-helical domain and deacetylated the K249 residue of PARP1. Furthermore, SIRT2 promoted ubiquitination of the K249 residue of PARP1 via mobilization of the E3 ubiquitin ligase WW domain-containing protein 2 (WWP2), which led to proteasome-mediated degradation of PARP1. Knockout of SIRT2 in mice and cells increased PARP1 acetylation and decreased PARP1 ubiquitination, which in turn aggravated oxidative stress-induced vascular injury and remodeling. Conversely, overexpression of SIRT2 in mice and cells decreased PARP1 acetylation, increased PARP1 ubiquitination, and relieved oxidative stress-induced vascular injury and remodeling. Overall, this study revealed a previously unrecognized mechanistic link between SIRT2 and PARP1 in the regulation of oxidative stress-induced vascular injury.
