Fc receptors (FcR) classically modulate responses to IgG in B cells and other effector cells in the immune system. We discovered that the inhibitory FcR, Fc?RIIB, is abundant in endothelium, and that it mediates endothelial NO synthase (eNOS) antagonism by IgG, C-reactive protein (CRP) and serum amyloid P component (SAP), which is the CRP-equivalent in mice. The eNOS antagonism occurs via inhibition of Akt and eNOS activating phosphorylation. Since in mice endothelial Akt and eNOS activating phosphorylation are similarly attenuated in association with obesity-induced hypertension (HTN), global Fc?RIIB-/- mice were placed on high-fat diet (HFD) and it was discovered that despite weight gain equal to that of Fc?RIIB+/+, the null mice are protected from obesity-induced HTN. The OVERALL GOAL of the proposal is to determine how Fc?RIIB contributes to the pathogenesis of obesity-induced HTN.
Aim 1 is to determine how endothelial cell Fc?RIIB participates in the disorder. Using radiotelemetry, BP will be compared in wild-type mice vs. mice with endothelial cell-specific Fc?RIIB deletion on normal chow vs. HFD. HFD-induced changes in vascular Akt and eNOS phosphorylation state will be evaluated in these groups, and potential protection from the HTN will be assessed in mice expressing constitutively-active Akt selectively in endothelium. An anti-Fc?RIIB blocking antibody will be used to determine if an intervention targeting the receptor prevents the HTN.
Aim 2 is to identity the Fc?RIIB ligand(s) mediating obesity-induced HTN. We've discovered that SAP increases in mice on HFD, and that IgG isolated from HFD-fed mice potently antagonizes eNOS in cultured endothelium, whereas IgG from normal chow-fed mice does not. HFD-induced HTN will therefore be studied in wild-type vs. SAP-/- and immunoglobulin u heavy-chain null mice deficient in B cells and IgG. If this work implicates IgG, a B cell depleting antibody and an FcRn-directed agent that enhances IgG degradation will be used to determine if interventions that decrease Fc?RIIB ligand abundance prevent obesity-induced HTN.
Aim 3 is to determine how Fc?RIIB influences the development of HTN in humans with elevated pentraxin levels or obesity. The association between common single nucleotide polymorphisms (SNP) in Fc?RIIB and incident HTN will be evaluated in the Women's Genome Health Study, which is a prospective cohort study of over 25,000 women. Impetus includes the discovery of an Fc?RIIB variant incapable of eNOS antagonism and a preliminary query of subjects with CRP>2.0mg/L in the Dallas Heart Study;in African Americans in whom genotype frequency provided sufficient statistical power, the loss-of-function variant was associated with lower systolic BP. By accomplishing these aims, the novel concept will be tested that Fc?RIIB in endothelium and FcR ligands participate in the pathogenesis of HTN. Unique preventative or treatment measures to combat the HTN that complicates obesity and other chronic inflammatory conditions will potentially follow.
We recently discovered that circulating mediators of inflammatory response have direct adverse actions on the endothelial cells that line blood vessels by binding to a cell surface receptor previously only known to be present on white blood cells. This process may play a major role in inflammation- related high blood pressure, such as occurs in the setting of obesity. In the proposed research program, we will determine how this receptor, known as Fc?RIIB, causes high blood pressure in obese mice, and we will use a genetic strategy to determine whether similar processes are operative in humans.