CaMKII regulates key mechanisms of vascular response to injury in vivo

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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 neointima formation and remodeling after vascular injury. Neointima formation and remodeling occur in vein graft failure after coronary artery bypass surgery, after balloon angioplasty and surgical endarterectomy and have a significant impact in terms of morbidity and health care cost. Our long-term goal is to study the function of CaMKII in the vasculature, specifically CaMKII modulation as new approach to treat vascular injury. The objective of this application is to determine how CaMKII is activated in injury, directy test whether CaMKII inhibition will confer disease resistance in vascular injury and delineate the dependance of VSMC migration and proliferation upon the oxidative activation of CaMKII. The central hypothesis of this application is that CaMKII is activated by oxidation of Met281/282 in vascular injury and that oxidative activation of CaMKII is necessary for neointimal hyperplasia, VSMC proliferation and migration. This hypothesis is based on our preliminary data that CaMKII is essential in neointima formation and remodeling after injury. Oxidized CaMKII (ox-CaMKII) is readily detected in the neointima after vascular injury. In addition, we have compelling evidence that key activators in the response to injury induce ox-CaMKII in vitro. The rationale of the proposed research is that understanding how CaMKII is activated after vascular injury, has the potential to translate into better strategies to prevent the deleterious effects after vascular injry. Guided by strong preliminary data, the central hypothesis will be tested in three specific aims: 1) Dissect the mechanisms of CaMKII activation in vascular injury in vivo; 2) Determine the role of methionine sulfoxide reductase A (MsrA), the enzyme that controls the balance between active ox-CaMKII and reduced inactive CaMKII, in the response to injury; 3) Dissect the mechanisms of CaMKII activation in VSMC migration, proliferation in vitro. In the first aim, a novel in vivo model will be used to test if the blockade of oxidative CaMKII activation is sufficient to abrogate the response to injury. Under aim 2, we will define whether MsrA can modulate neointimal hyperplasia through ox-CaMKII. In aim 3, we will delineate how CaMKII is activated by key cytokines and growth factors relevant for vascular injury in vitro and how the activation pathways correlate with VSMC migration and proliferation. 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 identifying CaMKII activating events in vivo. Ultimately, such knowledge may allow for the development of new preventive strategies for vascular injury.