A Novel Multifunctional Role for CaMKIIg in Advanced Atherosclerosis

Atherosclerosis is a heterogeneous disease in which only a small fraction of lesions lead to heart attack, stroke, or sudden cardiac death. The type of plaque that often precipitates these events contains large necrotic cores, thin fibrous caps and extensive inflammation. Studies over the last decade suggest that failed resolution of a chronic inflammatory response is an important driver in the progression of atherosclerosis. My preliminary data show that Ca2+/calmodulin-dependent protein kinase gamma (CaMKIIg) in macrophages plays a major role in the development of necrotic, thin-capped plaques. Mechanistic studies revealed that CaMKIIg-deficient macrophages and atherosclerotic lesions lacking myeloid CaMKIIg have increased expression of Activating Transcription Factor-6 (ATF6) and that ATF6 induces the transcription factor liver X receptor-alpha (LXRa). In turn, LXRa upregulates the expression of MerTK, which plays a key role in the clearance of apoptotic cells, production of inflammatory mediators, and development of the necrotic core. The overall objective of this proposal is to understand the mechanisms by which CaMKIIg increases inflammation thereby promoting advanced atherosclerosis. In Aim 1, I will explore the mechanism by which CaMKII regulates the production of pro-resolving and pro-inflammatory lipid mediators in vitro and in vivo. Using myeloid-CaMKIIg KO mice, I will examine a novel mechanism by which CaMKIIg regulates the cellular localization of lipoxygenases in order to produce pro-inflammatory lipid mediators at the expense of pro-resolving mediators. Aim 2 will investigate the hypothesis that CaMKII regulates production of protein mediators of inflammation (i.e. IL-1beta, IL-6, etc.) through both LXR-dependent and LXR-independent signaling pathways. Using mice with myeloid lineage deficiency of both CaMKIIg and LXRa, I will explore the impact of these mechanisms both in vitro and in vivo. Finally, in Aim 3, I will test the hypothesis that silencing of CaMKII in plaque macrophages will promote plaque regression. In a model of rapid lipid lowering using adenoviral delivery of LDLR to Western diet-fed Ldlr-/- mice, I will examine the impact of myeloid CaMKIIg on the regression of advanced plaque characteristics. This research will be accomplished in the setting of a comprehensive career development plan designed to provide the skills needed for me to become an independent physician-scientist in cardiovascular research. (AHA Program: Fellow-to-Faculty Transition Award)