Sunday, April 28, 2024
4/28/2024
Plasma HDL levels are inversely associated with coronary, cerebral and peripheral arterial disease (PAD), and also type 2 diabetes mellitus (T2DM). However, how HDL influences these conditions remains poorly understood. We previously showed that HDL attenuates vascular inflammation and promotes neovascularization via scavenger receptor class B type I (SR-BI) and its adaptor protein PDZK1 in endothelial cells (EC). We recently identified Breakpoint Cluster Region (BCR) protein as a novel PDZK1 interacting protein in human EC. In other contexts BCR has known functions modulating Rac1 and RhoA, and we discovered it to be a novel kinase for Akt kinase activated by HDL in EC. Our studies in BCR null mice then revealed for the first time that BCR is required for HDL-related atheroprotection, HDL-induced endothelial repair and angiogenesis, and normal glucose homeostasis. The Overall Goal of the present project is to determine HOW BCR actions in EC contribute to HDL-related atheroprotection and promotion of neovascularization and normal glucose homeostasis. Three Aims are proposed in cultured EC and mice. Aim 1 will determine how endothelial BCR impacts atherosclerosis. We recently discovered in culture that BCR is necessary for HDL attenuation of both the monocyte-EC adhesion and the Rac1-dependent EC LDL transport that converge to drive atherogenesis. Using cultured EC, floxed BCR mice, and nanoparticle-based EC cDNA delivery to reconstitute EC wild-type or mutant BCR expression in vivo, we will test the hypothesis that HDL-related atheroprotection is mediated by EC BCR and its capacity to function as a kinase or inhibitor of Rac1. In cultured EC we will also query how HDL subspecies with varying Apo-A1 and Apo-A2 content and size impact BCR-dependent atheroprotective processes. Aim 2 will determine how EC BCR impacts neovascularization, which is critical to PAD pathogenesis and resolution. We recently showed that EC migration prompted by HDL is BCR-dependent. Using cultured EC, floxed BCR mice, reconstitution of EC BCR in vivo, and mouse models of EC repair, angiogenesis and hindlimb ischemia, we will test the hypothesis that EC BCR function as a kinase or an activator of RhoA underlies HDL-induced neovascularization. In culture, how HDL subspecies impact EC neovascularization mechanisms will also be examined. Aim 3 will determine how EC BCR impacts glucose control. Knowing that HDL has antidiabetic action and that EC insulin transport to skeletal muscle drives processes underlying 80-90% of total body glucose disposal, we have discovered that HDL stimulates EC insulin transport via BCR. Using cultured EC, floxed BCR mice, reconstitution of EC BCR and glucose control phenotyping in vivo, we will test the hypothesis that EC BCR function as an Akt kinase kinase underlies HDL promotion of normal glucose homeostasis. In culture, how HDL subspecies impact EC insulin transport will also be studied. The proposed work providing new insights into how HDL affords cardiometabolic protection has the potential to add clarity to why HDL has varying impact on individuals, and to reveal new therapeutic targets to leverage against cardiovascular and metabolic disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
