Role of FKBP12/12.6 in Endothelial Function

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DESCRIPTION (provided by applicant): Immunosuppressive drugs reduce the incidence of organ rejection following transplantation, however these drugs can cause endothelial dysfunction and hypertension. Our long-term goal is to elucidate the mechanisms by which the immunosuppressive drugs rapamycin and FK506 decrease nitric oxide (NO) and increase blood pressure so that future drugs can be developed that do not promote hypertension and cardiovascular disease. We hypothesize that these effects arise from removal of FKBP12/12.6 from intracellular calcium release channels resulting in increased basal endothelial cell calcium levels and phosphorylation of endothelial NO synthase (eNOS). To test this hypothesis we will: 1) Determine the effects of FKBP12/12.6 depletion on intracellular calcium homeostasis, 2) Determine the role of cPKC in eNOS phosphorylation, NO production, and blood pressure elevation following alterations of FKBP12/12.6, and 3) Assess the role of FKBP12/12.6 in endothelial function and blood pressure regulation. We will use a combination of pharmacologic and/or genetic perturbations of FKBP12/12.6 and measure the effects on blood pressure, endothelium-dependent dilation, NO production, and eNOS and PKC expression and phosphorylation. We will also measure how FKBP12/12.6 depletion in endothelial cells alters intracellular calcium homeostasis including changes in the magnitude, duration, and location of intracellular calcium mobilization. Drugs that suppress the immune system are extremely important following organ transplantation, however these drugs can cause high blood pressure. Our research will use various genetically altered mice and techniques to understand the mechanisms of how this happens in hopes of developing future immunosuppressive drugs that will not have negative cardiovascular side effects.