title: Ca2+/calmodulin-dependent protein kinase II-γ (CaMKIIγ) negatively regulates vascular smooth muscle cell proliferation and vascular remodeling.
abstract: Vascular smooth muscle (VSM) expresses calcium/calmodulin-dependent protein kinase II (CaMKII)-δ and -γ isoforms. CaMKIIδ promotes VSM proliferation and vascular remodeling. We tested CaMKIIγ function in vascular remodeling after injury. CaMKIIγ protein decreased 90% 14 d after balloon injury in rat carotid artery. Intraluminal transduction of adenovirus encoding CaMKIIγC rescued expression to 35% of uninjured controls, inhibited neointima formation (>70%), inhibited VSM proliferation (>60%), and increased expression of the cell-cycle inhibitor p21 (>2-fold). Comparable doses of CaMKIIδ2 adenovirus had no effect. Similar dynamics in CaMKIIγ mRNA and protein expression were observed in ligated mouse carotid arteries, correlating closely with expression of VSM differentiation markers. Targeted deletion of CaMKIIγ in smooth muscle resulted in a 20-fold increase in neointimal area, with a 3-fold increase in the cell proliferation index, no change in apoptosis, and a 60% decrease in p21 expression. In cultured VSM, CaMKIIγ overexpression induced p53 mRNA (1.7 fold) and protein (1.8-fold) expression; induced the p53 target gene p21 (3-fold); decreased VSM cell proliferation (>50%); and had no effect on expression of apoptosis markers. We conclude that regulated CaMKII isoform composition is an important determinant of the injury-induced vasculoproliferative response and that CaMKIIγ and -δ isoforms have nonequivalent, opposing functions.
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; and Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Fatima Z
authors.initials: FZ
authors.lastname: Saddouk
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; and Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Sun
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; and Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Yong Feng
authors.initials: YF
authors.lastname: Liu
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; and Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Miao
authors.initials: M
authors.lastname: Jiang
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; and Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Diane V
authors.initials: DV
authors.lastname: Singer
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; and Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; and Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Dee
authors.initials: D
authors.lastname: Van Riper
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; and Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Ginnan
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; and Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: John J
authors.initials: JJ
authors.lastname: Schwarz
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; and Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany singerh@mail.amc.edu.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Singer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000502:physiology*; D058426:Neointima / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: D015415:Biomarkers; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Camk2d; Camk2g; restenosis