Calmodulin kinase II inhibition as novel molecular treatment of hypertension

Iowa City Va Medical Center, Iowa City IA

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Abstract

DESCRIPTION (provided by applicant): 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.