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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL084299-02S1
Application #
7839416
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Goldman, Stephen
Project Start
2009-07-15
Project End
2011-11-30
Budget Start
2009-07-15
Budget End
2011-11-30
Support Year
2
Fiscal Year
2009
Total Cost
$202,670
Indirect Cost
Name
Texas A&M University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Chiasson, Valorie L; Pakanati, Abhinandan R; Hernandez, Marcos et al. (2017) Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor-Induced Hypertension in Mice. Hypertension 70:183-191
Nguyen, Hoanglan; Chiasson, Valorie L; Chatterjee, Piyali et al. (2013) Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension. Cardiovasc Res 97:696-704
Chiasson, Valorie L; Jones, Kathleen A; Kopriva, Shelley E et al. (2012) Endothelial cell transforming growth factor-? receptor activation causes tacrolimus-induced renal arteriolar hyalinosis. Kidney Int 82:857-66
Chiasson, Valorie L; Talreja, Deepa; Young, Kristina J et al. (2011) FK506 binding protein 12 deficiency in endothelial and hematopoietic cells decreases regulatory T cells and causes hypertension. Hypertension 57:1167-75
Chiasson, Valorie L; Munshi, Nidhi; Chatterjee, Piyali et al. (2011) Pin1 deficiency causes endothelial dysfunction and hypertension. Hypertension 58:431-8
Chiasson, Valorie L; Quinn, Matthew A; Young, Kristina J et al. (2011) Protein kinase CbetaII-mediated phosphorylation of endothelial nitric oxide synthase threonine 495 mediates the endothelial dysfunction induced by FK506 (tacrolimus). J Pharmacol Exp Ther 337:718-23
Cook, Leslie G; Chiasson, Valorie L; Long, Cheng et al. (2009) Tacrolimus reduces nitric oxide synthase function by binding to FKBP rather than by its calcineurin effect. Kidney Int 75:719-26
Tinsley, John H; Chiasson, Valorie L; Mahajan, Ashutosh et al. (2009) Toll-like receptor 3 activation during pregnancy elicits preeclampsia-like symptoms in rats. Am J Hypertens 22:1314-9
Tinsley, John H; Chiasson, Valorie L; South, Sanique et al. (2009) Immunosuppression improves blood pressure and endothelial function in a rat model of pregnancy-induced hypertension. Am J Hypertens 22:1107-14