The function of the multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII) remains poorly understood in the vasculature. Our data suggest that CaMKII is instrumental in mediating blood pressure increases in Angiotensin-II (Ang-II) hypertension. Thus, CaMKII inhibition may be a potent novel approach to treat high blood pressure. Almost 50% of the veterans that are currently receiving health care through the VA carry the diagnosis of hypertension. The average treatment cost associated with this diagnosis has been estimated at $6,000 per veteran annually. Nonetheless, about 30% of veterans with hypertension currently do not reach the target blood pressure (BP). Our long-term goal is to help develop selective CaMKII inhibitors that can be used clinically for the treatment of hypertension. As a next step toward this goal, the objective of this application is to delineate the function of CaMKII in established models of hypertension. The central hypothesis is that CaMKII activity in vascular smooth muscle cells regulates vascular tone by increasing intracellular Ca2+ and thereby BP. Our hypothesis is based on strong preliminary data obtained in our novel in vivo mouse model in which the potent and specific endogenous CaMKII inhibitor CaMKIIN is selectively overexpressed in smooth muscle cells. Our Tg SM HA-CaMKIIN mice exhibit significantly decreased blood pressure in Ang-II-induced hypertension. The rationale for the proposed studies is that, once we understand how CaMKII regulates intracellular Ca2+ and thereby affects vascular smooth muscle cell contraction and blood pressure, we will have made a critical first step towards assessing its potential as a new molecular target for the development of drugs to treat hypertension. Guided by strong preliminary data, the central hypothesis will be tested in two specific aims: 1) Identify the effect that CaMKII inhibition in vascular smooth muscle cells has on blood pressure in established models of hypertension, 2): Identify how CaMKII controls the intracellular Ca2+ load of vascular smooth muscle cells. In the first aim, the novel in vivo model will be used to test whether CaMKII activation is a common pathway in three blood pressure models and if CaMKII inhibition is sufficient to abrogate the BP increases.
Under aim 2, we will define the mechanisms through which CaMKII controls intracellular intracellular Ca2+ in vascular smooth muscle cells. The approach is innovative because of its use of novel in vivo models and specific tools to dissect CaMKII signaling. The proposed research is significant because it is expected to advance the field by defining CaMKII as a novel molecular target that controls intracellular Ca2+ and vascular tone. Ultimately, such knowledge may allow for the development of new therapeutic strategies in hypertension that will benefit our veterans.

Public Health Relevance

More than 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 medications for hypertension do not reach their blood pressure treatment goals. The proposed research aims at understanding a recently discovered key regulator of vascular tone and blood pressure with the ultimate goal to develop its inhibitor as new treatment strategies for hypertension. The proposed research is directly relevant to VA healthcare because of the high disease burden and enormous health care cost that hypertension is causing in veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000163-07
Application #
8974221
Study Section
Cardiovascular Studies A (CARA)
Project Start
2009-04-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Iowa City VA Medical Center
Department
Type
DUNS #
028084333
City
Iowa City
State
IA
Country
United States
Zip Code
52246
Nguyen, Emily K; Koval, Olha M; Noble, Paige et al. (2018) CaMKII (Ca2+/Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation. Arterioscler Thromb Vasc Biol 38:1333-1345
Pennington, Steven M; Klutho, Paula R; Xie, Litao et al. (2018) Defective protein repair under methionine sulfoxide A deletion drives autophagy and ARE-dependent gene transcription. Redox Biol 16:401-413
Murthy, Shubha; Koval, Olha M; Ramiro Diaz, Juan M et al. (2017) Endothelial CaMKII as a regulator of eNOS activity and NO-mediated vasoreactivity. PLoS One 12:e0186311
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
Gu, Sean X; Blokhin, Ilya O; Wilson, Katina M et al. (2016) Protein methionine oxidation augments reperfusion injury in acute ischemic stroke. JCI Insight 1:
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

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