The Department of Veterans Affairs spent more than $150 million dollars on treatment of hypertension in 2000. However, only 50 % of all veterans achieve their blood pressure goals often despite polypharmacy. There is a clear need to develop new treatment strategies for controlling hypertension. The multifunctional calcium/ calmodulin-dependent kinase II (CaMKII) is abundantly expressed in vascular smooth muscle (VSM), however, its role in VSM function has not been intensively investigated. We have developed new, state of the art techniques to study CaMKII function in vascular smooth muscle in vitro and in vitro. Our preliminary data suggest CaMKII as a key regulator in hypertension. Specifically, our preliminary studies show that (1) CaMKII inhibition reduces vascular smooth muscle hypertrophy in vivo and in vitro, and (2) vasoconstrictor response in aorta and resistance blood vessels. (3) Systemic CaMKII blockade reduces Ang-II hypertension. Based on these findings, we hypothesize that (1) CaMKII inhibition in VSM in vivo decreases vascular hypertrophy and vasoconstrictor response in hypertension, (2) CaMKII is required for VSM cell hypertrophy, (2) that CaMKII induces VSM cell hypertrophy by HDAC4 derepression. We will combine a number of complementary, state of the art techniques (molecular biology, protein chemistry, cell signaling and physiology, animal physiology) to dissect the components of CaMKII signaling in VSM and the effect of CaMKII on hypertension and medial hypertrophy in vivo. All of these techniques are at hand in our laboratory or the laboratories of our collaborators.

Public Health Relevance

Potential Impact on Veterans Health Care Cardiovascular diseases are the most frequent causes of death in the US. Hypertension is an important risk factor for the development of atherosclerosis, stroke and heart failure. Overall, 1.6 million veterans were treated for hypertension in 2002. In 2000, the VA spent an estimated 150 million dollars on antihypertensives alone. Despite these efforts, 50% of all veterans on treatment for hypertension do not reach their blood pressure treatment goals. There is still a pressing need for developing new concepts to treat hypertension. This proposal is aimed at investigating the role of the multifunctional calcium/calmodulin-dependent kinase II (CaMKII) in hypertension, vasomotor response and vascular smooth muscle hypertrophy. Inhibition of CaMKII could represent a novel approach to treating hypertension and preventing vascular remodeling.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000163-02
Application #
8195605
Study Section
Cardiovascular Studies A (CARA)
Project Start
2010-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
Indirect Cost
Name
Iowa City VA Medical Center
Department
Type
DUNS #
028084333
City
Iowa City
State
IA
Country
United States
Zip Code
52245
Winters, Christopher J; Koval, Olha; Murthy, Shubha et al. (2016) CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis. Am J Physiol Lung Cell Mol Physiol 310:L86-94
Prasad, Anand M; Ketsawatsomkron, Pimonrat; Nuno, Daniel W et al. (2016) Role of CaMKII in Ang-II-dependent small artery remodeling. Vascul Pharmacol 87:172-179
Prasad, Anand M; Morgan, Donald A; Nuno, Daniel W et al. (2015) Calcium/calmodulin-dependent kinase II inhibition in smooth muscle reduces angiotensin II-induced hypertension by controlling aortic remodeling and baroreceptor function. J Am Heart Assoc 4:e001949
Klutho, Paula J; Pennington, Steven M; Scott, Jason A et al. (2015) Deletion of Methionine Sulfoxide Reductase A Does Not Affect Atherothrombosis but Promotes Neointimal Hyperplasia and Extracellular Signal-Regulated Kinase 1/2 Signaling. Arterioscler Thromb Vasc Biol 35:2594-604
Zhu, Linda J; Klutho, Paula J; Scott, Jason A et al. (2014) Oxidative activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) regulates vascular smooth muscle migration and apoptosis. Vascul Pharmacol 60:75-83
Scott, Jason A; Klutho, Paula J; El Accaoui, Ramzi et al. (2013) The multifunctional Ca²?/calmodulin-dependent kinase II? (CaMKII?) regulates arteriogenesis in a mouse model of flow-mediated remodeling. PLoS One 8:e71550
Prasad, Anand M; Nuno, Daniel W; Koval, Olha M et al. (2013) Differential control of calcium homeostasis and vascular reactivity by Ca2+/calmodulin-dependent kinase II. Hypertension 62:434-41