title: The multifunctional Ca2+/calmodulin-dependent kinase II delta (CaMKIIdelta) controls neointima formation after carotid ligation and vascular smooth muscle cell proliferation through cell cycle regulation by p21.
abstract: The multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) promotes vascular smooth muscle (VSMC) proliferation. However, the signaling pathways mediating CAMKII-dependent proliferative effects in vivo are poorly understood. This study tested the hypothesis that CaMKIIδ mediates neointimal proliferation after carotid artery ligation by regulating expression and activity of cell cycle regulators, particularly at the G1/S checkpoint. Data herein indicate that 14 days after carotid ligation, C57Bl/6 mice developed a marked neointima with robust CaMKII protein expression. In particular, only the CaMKII isoform δ was increased as demonstrated by quantitative RT-PCR. Genetic deletion of CaMKII δ prevented injury-induced neointimal hyperplasia and cell proliferation in the intima and media. In ligated carotids of control mice, the proliferative cell cycle markers cdk2, cyclin E, and cyclin D1 were activated. In contrast, in CaMKIIδ(-/-) mice, we detected a reduction in proliferative cell cycle regulators as well as an increase in the cell cycle inhibitor p21. This expression profile was confirmed in cultured CaMKIIδ(-/-) VSMC, in which cdk2 and cdk4 activity was decreased. Toward understanding how CAMKIIδ affects p53, a transcriptional regulator of p21, we examined p53 pathway components. Our data indicate that p53 is elevated in CAMKIIδ(-/-) VSMC, whereas phosphorylation of the p53-specific E3 ligase, Mdm2, was decreased. In conclusion, CaMKII stimulates neointima proliferation after vascular injury by regulating cell proliferation through inhibition of p21 and induction of Mdm-2-mediated degradation of p53.
authors.affiliation: From the Division of Cardiovascular Medicine/Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.affiliation: From the Division of Cardiovascular Medicine/Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: From the Division of Cardiovascular Medicine/Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Sanders
authors.affiliation: From the Division of Cardiovascular Medicine/Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: the Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany, and.
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.affiliation: the Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: From the Division of Cardiovascular Medicine/Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: From the Division of Cardiovascular Medicine/Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa,; the Iowa City VA Medical Center, Iowa City, Iowa 52242,. Electronic address: isabella-grumbach@uiowa.edu.
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Grumbach
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D058426:Neointima / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016196:S Phase; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4