title: p55γ functional mimetic peptide N24 blocks vascular proliferative disorders.
abstract: Proliferation and migration disorders of vascular smooth muscle cells (VSMCs) contribute to the pathogenesis of proliferative cardiovascular diseases. Although, over the past two decades, a large panel of drugs has been developed for targeting VSMC proliferation, cardiovascular disease remains the leading cause of death worldwide. Thus, there is a compelling need to identify novel signaling pathways and molecules controlling VSMC proliferation and migration, to provide not only mechanistic insights but also safe and effective therapies for the treatment of cardiovascular diseases. Our recent studies have demonstrated that p55γ, a regulatory subunit of phosphoinositide 3-kinase, functions as an endogenous brake on VSMC proliferation. Here, we demonstrate that the small peptide N24, the first 24 amino acids of the NH2 terminus of p55γ, is a functional mimetic which negatively regulates VSMC proliferation and migration. Specifically, luminal delivery of adenovirus expressing N24 or local administration of Tat transactivator protein (TAT)-tagged N24 by pluronic gel alleviates neointimal formation following balloon injury in rat carotid arteries. Enforced expression of N24 suppresses the proliferation and migration of VSMCs induced by serum- or platelet-derived growth factor-BB. Mechanistically, N24 induces cell cycle arrest via activating the p53-p21 signal pathway, without triggering cell death. N24 interacts with and stabilizes p53 by blocking its ubiquitin-dependent degradation, subsequently promotes p21 transcription, and arrests cell cycle progression. Indeed, knockdown of p21 or p53 abrogates the N24-mediated cell growth arrest. Thus, N24 is a p55γ mimetic inhibiting VSMC proliferation as well as migration, thereby conferring important therapeutic implications for anti-proliferative treatment.
  
  
  CONCLUSIONS
  • N24 attenuates balloon injury-induced neointimal formation. • Overexpression of N24 inhibits cultured VSMC proliferation and migration. • Overexpression of N24 arrests the cell cycle at S phase. • N24 interacts with and stabilizes p53 resulting in growth suppression.
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, 100871, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Guo
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, 100871, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Xie
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, 100871, China.
authors.forename: Geng
authors.initials: G
authors.lastname: Li
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, 100871, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, 100871, China.
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Lv
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, 100871, China.
authors.forename: Sile
authors.initials: S
authors.lastname: Guo
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, 100871, China.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, 100871, China. caochunmei@pku.edu.cn.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Cao
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, 100871, China. xiaor@pku.edu.cn.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, 100871, China. xiaor@pku.edu.cn.|Center for Life Sciences, Peking University, Beijing, 100871, China. xiaor@pku.edu.cn.|Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China. xiaor@pku.edu.cn.
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015696:Gene Products, tat / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D058426:Neointima / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
chemical_list: D015696:Gene Products, tat; C534878:N24 peptide, human; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; C523442:PIK3R3 protein, human
keywords: Migration; Neointimal formation; Proliferation; Restenosis; Vascular smooth muscle cells; p55γ