Calcium/calmodulin-dependent kinase II inhibition in smooth muscle reduces angiotensin II-induced hypertension by controlling aortic remodeling and baroreceptor function

Anand M Prasad; Donald A Morgan; Daniel W Nuno; Pimonrat Ketsawatsomkron; Thomas B Bair; Ashlee N Venema; Megan E Dibbern; William J Kutschke; Robert M Weiss; Kathryn G Lamping; Mark W Chapleau; Curt D Sigmund; Kamal Rahmouni; Isabella M Grumbach

doi:10.1161/JAHA.115.001949

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Calcium/calmodulin-dependent kinase II inhibition in smooth muscle reduces angiotensin II-induced hypertension by controlling aortic remodeling and baroreceptor function

Journal article

Open access

Calcium/calmodulin-dependent kinase II inhibition in smooth muscle reduces angiotensin II-induced hypertension by controlling aortic remodeling and baroreceptor function

Anand M Prasad, Donald A Morgan, Daniel W Nuno, Pimonrat Ketsawatsomkron, Thomas B Bair, Ashlee N Venema, Megan E Dibbern, William J Kutschke, Robert M Weiss, Kathryn G Lamping, …

Journal of the American Heart Association, Vol.4(6), pp.e001949-e001949

06/15/2015

DOI: 10.1161/JAHA.115.001949

PMCID: PMC4599535

PMID: 26077587

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Abstract

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. 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. CaMKII in VSMCs regulates blood pressure under Ang II hypertension by controlling structural gene expression, wall stiffness, and baroreceptor activity.

Angiotensin II - pharmacology

Antihypertensive Agents - pharmacology

Echocardiography

Oligonucleotide Array Sequence Analysis

Aorta - drug effects

Mice, Inbred C57BL

Pressoreceptors - physiology

Hypertension - drug therapy

Mice, Transgenic

Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors

Muscle, Smooth, Vascular - physiopathology

Norepinephrine - blood

Animals

Calcium-Calmodulin-Dependent Protein Kinase Type 2 - physiology

Hypertension - chemically induced

Vascular Remodeling - physiology

Mice

Vascular Remodeling - drug effects

Aorta - physiology

Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism

Muscle, Smooth, Vascular - drug effects

Pressoreceptors - drug effects

Details

Title: Subtitle: Calcium/calmodulin-dependent kinase II inhibition in smooth muscle reduces angiotensin II-induced hypertension by controlling aortic remodeling and baroreceptor function
Creators: Anand M Prasad - 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.)
Donald A Morgan - 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.)
Daniel W Nuno - 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.)
Pimonrat Ketsawatsomkron - 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.)
Thomas B Bair - The Iowa Institute for Human Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA (T.B.B.)
Ashlee N Venema - 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.)
Megan E Dibbern - 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.)
William J Kutschke - 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.)
Robert M Weiss - 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.)
Kathryn G Lamping - 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.)
Mark W Chapleau - 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.)
Curt D Sigmund - 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.)
Kamal Rahmouni - 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.)
Isabella M Grumbach - 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.)
Resource Type: Journal article
Publication Details: Journal of the American Heart Association, Vol.4(6), pp.e001949-e001949
DOI: 10.1161/JAHA.115.001949
PMID: 26077587
PMCID: PMC4599535
NLM abbreviation: J Am Heart Assoc
ISSN: 2047-9980
eISSN: 2047-9980
Publisher: England
Grant note: R01 HL 108932 / NHLBI NIH HHS I01 BX000543 / BLRD VA T32 HL007121 / NHLBI NIH HHS R01 HL108932 / NHLBI NIH HHS I01 BX000163 / BLRD VA P01 HL084207 / NHLBI NIH HHS HL1 4388 / NHLBI NIH HHS OD019941 / NIH HHS
Language: English
Date published: 06/15/2015
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984025306702771

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