Open AccessCalcium/Calmodulin‐Dependent Kinase II Inhibition in Smooth Muscle Reduces Angiotensin II–Induced Hypertension by Controlling Aortic Remodeling and Baroreceptor Function
Author(s) -
Prasad Anand M.,
Morgan Donald A.,
Nuno Daniel W.,
Ketsawatsomkron Pimonrat,
Bair Thomas B.,
Venema Ashlee N.,
Dibbern Megan E.,
Kutschke William J.,
Weiss Robert M.,
Lamping Kathryn G.,
Chapleau Mark W.,
Sigmund Curt D.,
Rahmouni Kamal,
Grumbach Isabella M.
Publication year - 2015
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.115.001949
Subject(s) - medicine , endocrinology , baroreceptor , angiotensin ii , blood pressure , vascular smooth muscle , angiotensin ii receptor type 1 , heart rate , smooth muscle
Background Multifunctional calcium/calmodulin‐dependent kinase II (Ca MKII ) 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 Ca MKII inhibition selectively in VSMCs on Ang II hypertension. Methods and Results Transgenic expression of a Ca MKII peptide inhibitor in VSMCs ( TG SM ‐Ca MKIIN 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 ‐Ca MKIIN 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 ‐Ca MKIIN mice. Moreover, examination of blood pressure and heart rate under ganglionic blockade revealed that VSMC Ca MKII inhibition abolished the augmented efferent sympathetic outflow and renal and splanchnic nerve activity in Ang II hypertension. Consequently, we hypothesized that VSMC Ca MKII 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 ‐Ca MKIIN aortas were protected from Ang II –induced upregulation of genes that control extracellular matrix production, including collagen. VSMC Ca MKII 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.