Despite multiple initiatives in the VA healthcare system, at least 30% of the estimated three million Veterans with hypertension do not reach the current target blood pressure (BP). Hypertension induces pathological remodeling of the vascular wall, leading to further increases in BP and end organ dysfunction. These effects are linked to 5,000 annual deaths among Veterans. Emerging data suggest that mitochondrial ROS production is a common denominator in hypertension, but mechanistic concepts of how mitochondrial function in VSMC drives hypertension and remodeling are missing. Our group has made significant contributions to unraveling the function of the multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII) in the vasculature in vivo and defined previously unrecognized pathways by which CaMKII controls VSMC Ca2+ handling, remodeling and BP. Of note, CaMKII is present in mitochondria and believed to control mitochondrial matrix Ca2+ influx via the mitochondrial Ca2+ uniporter. We recently made the novel discovery that inhibition of CaMKII in VSMC is sufficient to block mitochondrial ROS production and prevent Angiotensin-II (Ang-II) hypertension. 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 hypertension-induced mitochondrial dysfunction. Here we propose to test the novel and innovative hypothesis that CaMKII contributes to a ROS-generating, pro- hypertensive feed forward circuit in vascular smooth muscle by actions in mitochondria. We have developed new genetic mouse models where we can conditionally and selectively control mitochondrial CaMKII in VSMC, which will be used to test the following three specific aims: 1) Dissect the molecular pathways by which mitoCaMKII controls mitochondrial function and mitoROS production in VSMC. 2) Dissect the mechanisms by which mitoCaMKII inhibition in VSMC protects against vascular wall remodeling and hypertension by Ang-II. 3) Establish the therapeutic potential of mitoCaMKII inhibition in a model of chronic hypertension.
Aim 1 will provide the cellular mechanisms through which CaMKII controls mitochondrial function. Data from aim 2 will determine pathways by which mitochondrial CaMKII in VSMC drives BP increases through mitochondrial ROS, whereas aim 3 will directly test whether mitochondrial CaMKII inhibition in VSMC can be used as treatment in hypertension. The approach is innovative because of its use of novel in vivo models and specific tools to dissect mitochondrial function. The proposed research is significant because it is expected to advance the field by defining a novel molecular target for antihypertensive therapy. Ultimately, such knowledge may allow for the development of new therapeutic strategies in hypertension that will benefits our Veterans.

Public Health Relevance

About 3 million veterans are treated for hypertension. The VA healthcare system spends an estimated 150 million dollars on antihypertensive therapy every year. Despite these efforts, at least 30% of all veterans who receive medications for hypertension do not reach their blood pressure treatment goals. The proposed research aims at understanding a recently discovered key regulator of blood pressure with the ultimate goal to develop its inhibitor as new mechanism-based treatment 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 #
2I01BX000163-08A1
Application #
9346799
Study Section
Cardiovascular Studies B (CARB)
Project Start
2010-07-01
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
8
Fiscal Year
2017
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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