Poldip2 knockdown inhibits vascular smooth muscle proliferation and neointima formation by regulating the expression of PCNA and p21

• Authors: Srinivasa Raju Datla, Emory University; Lula Hilenski, Emory University; Bonnie Seidel-Rogol, Emory University; Anna E. Dikalova, Emory University; Mark Harousseau, Emory University; Lili Punkova, Emory University; Giji Joseph, Emory University; W Robert Taylor, Emory University; Bernard Lassegue, Emory University; Kathy Griendling, Emory University
• Journal Title: Laboratory Investigation
• Volume: Volume 99, Number 3
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals | 2019-03-01, Pages 387-398
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/s41374-018-0103-y
• Subjects: Health Sciences, General; Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Pathology; Research & Experimental Medicine; DELTA-INTERACTING PROTEIN-2; DNA-POLYMERASE-DELTA; CYCLIN-DEPENDENT KINASES; CELL NUCLEAR ANTIGEN; REACTIVE OXYGEN; NADPH OXIDASE; NOX4; BINDING; ARREST; DEGRADATION

Abstract

Polymerase delta-interacting protein 2 (Poldip2) is a multi-functional protein with numerous roles in the vasculature, including the regulation of cell apoptosis and migration, as well as extracellular matrix deposition; however, its role in VSMC proliferation and neointimal formation is unknown. In this study, we investigated the role of Poldip2 in intraluminal wire-injury induced neointima formation and proliferation of vascular smooth muscle cells in vitro and in vivo. Poldip2 expression was observed in the intima and media of human atherosclerotic arteries, where it colocalized with proliferating cell nuclear antigen (PCNA). Wire injury of femoral arteries of Poldip2 +/+ mice induced robust neointimal formation after 2 weeks, which was impaired in Poldip2 +/‒ mice. PCNA expression was significantly reduced and expression of the cell cycle inhibitor p21 was significantly increased in wire-injured arteries of Poldip2 +/‒ animals compared to wild-type controls. No difference was observed in apoptosis. Downregulation of Poldip2 in rat aortic smooth muscle cells significantly reduced serum-induced proliferation and PCNA expression, but upregulated p21 expression. Downregulation of p21 using siRNA reversed the inhibition of proliferation induced by knockdown of Poldip2. These results indicate that Poldip2 plays a critical role in the proliferation of VSMCs.