title: Calcium/calmodulin-dependent kinase II inhibition in smooth muscle reduces angiotensin II-induced hypertension by controlling aortic remodeling and baroreceptor function.
abstract: BACKGROUND
  Multifunctional calcium/calmodulin-dependent kinase II (CaMKII) is activated by angiotensin II (Ang II) in cultured vascular smooth muscle cells (VSMCs), but its function in experimental hypertension has not been explored. The aim of this study was to determine the impact of CaMKII inhibition selectively in VSMCs on Ang II hypertension.
  
  
  RESULTS
  Transgenic expression of a CaMKII peptide inhibitor in VSMCs (TG SM-CaMKIIN model) reduced the blood pressure response to chronic Ang II infusion. The aortic depressor nerve activity was reset in hypertensive versus normotensive wild-type animals but not in TG SM-CaMKIIN mice, suggesting that changes in baroreceptor activity account for the blood pressure difference between genotypes. Accordingly, aortic pulse wave velocity, a measure of arterial wall stiffness and a determinant of baroreceptor activity, increased in hypertensive versus normotensive wild-type animals but did not change in TG SM-CaMKIIN mice. Moreover, examination of blood pressure and heart rate under ganglionic blockade revealed that VSMC CaMKII inhibition abolished the augmented efferent sympathetic outflow and renal and splanchnic nerve activity in Ang II hypertension. Consequently, we hypothesized that VSMC CaMKII controls baroreceptor activity by modifying arterial wall remodeling in Ang II hypertension. Gene expression analysis in aortas from normotensive and Ang II-infused mice revealed that TG SM-CaMKIIN aortas were protected from Ang II-induced upregulation of genes that control extracellular matrix production, including collagen. VSMC CaMKII inhibition also strongly altered the expression of muscle contractile genes under Ang II.
  
  
  CONCLUSIONS
  CaMKII in VSMCs regulates blood pressure under Ang II hypertension by controlling structural gene expression, wall stiffness, and baroreceptor activity.
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (A.M.P., D.W.N., A.N.V., M.E.D., W.J.K., R.M.W., K.G.L., M.W.C., C.D.S., K.R., I.M.G.).
authors.forename: Anand M
authors.initials: AM
authors.lastname: Prasad
authors.affiliation: Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA (D.A.M., D.W.N., P.K., K.G.L., C.D.S., K.R.).
authors.forename: Donald A
authors.initials: DA
authors.lastname: Morgan
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (A.M.P., D.W.N., A.N.V., M.E.D., W.J.K., R.M.W., K.G.L., M.W.C., C.D.S., K.R., I.M.G.) Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA (D.A.M., D.W.N., P.K., K.G.L., C.D.S., K.R.).
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nuno
authors.affiliation: Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA (D.A.M., D.W.N., P.K., K.G.L., C.D.S., K.R.).
authors.forename: Pimonrat
authors.initials: P
authors.lastname: Ketsawatsomkron
authors.affiliation: The Iowa Institute for Human Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA (T.B.B.).
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Bair
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (A.M.P., D.W.N., A.N.V., M.E.D., W.J.K., R.M.W., K.G.L., M.W.C., C.D.S., K.R., I.M.G.) The Iowa City VA Healthcare System, Iowa City, IA (A.N.V., K.G.L., M.W.C., I.M.G.).
authors.forename: Ashlee N
authors.initials: AN
authors.lastname: Venema
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (A.M.P., D.W.N., A.N.V., M.E.D., W.J.K., R.M.W., K.G.L., M.W.C., C.D.S., K.R., I.M.G.).
authors.forename: Megan E
authors.initials: ME
authors.lastname: Dibbern
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (A.M.P., D.W.N., A.N.V., M.E.D., W.J.K., R.M.W., K.G.L., M.W.C., C.D.S., K.R., I.M.G.).
authors.forename: William J
authors.initials: WJ
authors.lastname: Kutschke
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (A.M.P., D.W.N., A.N.V., M.E.D., W.J.K., R.M.W., K.G.L., M.W.C., C.D.S., K.R., I.M.G.).
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (A.M.P., D.W.N., A.N.V., M.E.D., W.J.K., R.M.W., K.G.L., M.W.C., C.D.S., K.R., I.M.G.) Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA (D.A.M., D.W.N., P.K., K.G.L., C.D.S., K.R.) The Iowa City VA Healthcare System, Iowa City, IA (A.N.V., K.G.L., M.W.C., I.M.G.).
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Lamping
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (A.M.P., D.W.N., A.N.V., M.E.D., W.J.K., R.M.W., K.G.L., M.W.C., C.D.S., K.R., I.M.G.) The Iowa City VA Healthcare System, Iowa City, IA (A.N.V., K.G.L., M.W.C., I.M.G.).
authors.forename: Mark W
authors.initials: MW
authors.lastname: Chapleau
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (A.M.P., D.W.N., A.N.V., M.E.D., W.J.K., R.M.W., K.G.L., M.W.C., C.D.S., K.R., I.M.G.) Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA (D.A.M., D.W.N., P.K., K.G.L., C.D.S., K.R.) Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA (C.D.S.).
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (A.M.P., D.W.N., A.N.V., M.E.D., W.J.K., R.M.W., K.G.L., M.W.C., C.D.S., K.R., I.M.G.) Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA (D.A.M., D.W.N., P.K., K.G.L., C.D.S., K.R.).
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (A.M.P., D.W.N., A.N.V., M.E.D., W.J.K., R.M.W., K.G.L., M.W.C., C.D.S., K.R., I.M.G.) The Iowa City VA Healthcare System, Iowa City, IA (A.N.V., K.G.L., M.W.C., I.M.G.).
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Grumbach
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D004452:Echocardiography; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology; D009638:Norepinephrine / Q000097:blood; D020411:Oligonucleotide Array Sequence Analysis; D011311:Pressoreceptors / Q000187:drug effects* / Q000502:physiology; D066253:Vascular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D000959:Antihypertensive Agents; D000804:Angiotensin II; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D009638:Norepinephrine
keywords: angiotensin II; calcium/calmodulin‐dependent kinase II; hypertension; sympathetic nerve activity; vascular remodeling