Brett Mitchell, Ph.D.
Assistant Professor
Department of Internal Medicine
702 SW HK Dodgen Loop
Temple,
Texas 76504
Phone: 254-724-6267
Fax: 254-742-7181
Email: bmitchell@medicine.tamhsc.edu
Education and Post-Graduate Training
Brett Mitchell is an Assistant Professor of Internal Medicine at the Cardiovascular Research Institute (CVRI) located in Temple, Texas. He received his B.A. in Health Fitness/Biology from Gustavus Adolphus College in 1995, and his M.S. in Human Physiology from the University of Wisconsin-La Crosse in 1996. He received his Ph.D. in Physiology from the Medical College of Georgia in 2003 where he worked with Dr. Clinton Webb studying endothelial dysfunction and hypertension. His postdoctoral work was at Universities Space Research Association located at NASA’s Johnson Space Center in Houston, TX. Dr. Mitchell then joined the faculty of Baylor College of Medicine in the Department of Molecular Physiology and Biophysics where he began studying the role of immunophilins in endothelial function and blood pressure regulation. Dr. Mitchell joined the faculty at Texas A&M Health Science Center in July 2007.
Research Interests
Immunophilins, Endothelial Function, and Blood Pressure Regulation:
Immunosuppressive drugs markedly reduce the incidence of rejection in organ transplant recipients, however many of these drugs cause hypertension and cardiovascular disease. Our research focuses on understanding the molecular mechanisms involved in the endothelial dysfunction and blood pressure elevation caused by these drugs. We have shown that the immunosuppressive drugs FK506 (tacrolimus) and rapamycin (sirolimus), which both bind and inhibit a common immunophilin termed FKBP12/12.6, cause an endothelial intracellular calcium leak which leads to altered phosphorylation of endothelial nitric oxide synthase (eNOS) and decreased production of nitric oxide (NO), reduced vasodilation, and increased blood pressure. Blocking the calcium leak or PKC, the kinase that phosphorylates eNOS at an inhibitory site, can restore endothelial function. These findings reveal a novel role for immunophilins in the control of endothelial function and blood pressure regulation. The role of other immunophilins in endothelial function is currently being investigated in our lab.
Preeclampsia and Pregnancy-Induced Hypertension:
Another disease characterized by endothelial dysfunction that we study is preeclampsia (PE) and pregnancy-induced hypertension. PE affects ~7-10% of pregnancies and is a syndrome defined by the onset of hypertension and proteinuria during pregnancy. PE is a leading cause of maternal and fetal morbidity and mortality and women with PE are at a higher risk of developing cardiovascular disease later in life. We have shown previously that oxidative stress and eNOS uncoupling contributes to endothelial dysfunction and hypertension in an experimental model of PE. Currently, we are examining the role of the immune system in the development of PE and hypothesize that abnormal activation of the maternal immune system during pregnancy leads to PE.
Techniques:
Current integrative approaches used to study endothelial function and blood pressure regulation include generation and use of transgenic and chimeric mice, blood pressure measurements, vascular reactivity in isolated blood vessels, primary and cultured endothelial cells, live cell imaging, intracellular calcium imaging, and biochemical and molecular techniques.
Our findings will provide a better understanding of the molecular mechanisms involved in the regulation of endothelial function and blood pressure during normal and disease states. Additionally, we hope this information will aid in the identification of new therapeutic targets and generation of novel treatments for organ transplant recipients and women with PE.
Selected Publications
Tinsley JH, Chiasson VL, South S, Mahajan A, Mitchell BM. Immunosuppression ameliorates symptoms in a rat model of preeclampsia. J Hypertens 2009;(in review).
Cook LG*, Chiasson VL*, Long C, Wu GY, Mitchell BM. Mechanisms of FK506-induced decrease in nitric oxide production and endothelial function. Kidney Int 2009;(in press). [*these authors contributed equally]
Mitchell BM, Cook LG, Danchuk S, Puschett JB. Uncoupled eNOS and oxidative stress in a rat model of pregnancy-induced hypertension. Am J Hypertens 2007;20:1297-1304.
Long C, Cook LG, Wu GY, Mitchell BM. Removal of FK506 Binding Protein 12/12.6 from endothelial ryanodine receptors leads to an intracellular calcium leak and endothelial dysfunction. Arterioscler Thromb Vasc Biol 2007;27:1580-1586.
Long C, Cook LG, Hamilton SL, Wu GY, Mitchell BM. FK506 Binding Protein 12/12.6 depletion increases endothelial nitric oxide synthase threonine 495 phosphorylation and blood pressure. Hypertension 2007;49:569-576.
Mitchell BM, Wallerath T, Forstermann U. Animal models of hypertension. Methods Mol Med 2007;139:105-112.
Kannankeril PJ*, Mitchell BM*, Goonasekera SA*, Chelu MG, Zhang W, Sood S, Kearney DL, Danila C, De Biasi M, Wehrens XHT, Pautler RG, Roden DM, Taffet GE, Dirksen RT, Anderson ME, Hamilton SL. Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy. Proc Natl Acad Sci 2006;103:12179-12184. [*these authors contributed equally]
Mitchell BM, Webb RC. Glucocorticoid-induced hypertension and tetrahydrobiopterin (BH4), a common cofactor for the production of vasoactive molecules. Curr Hypertens Rev 2005;1:1-6.
Mitchell BM, Meck JV. Short-duration spaceflight does not prolong QTc intervals in male astronauts. Am J Cardiol 2004;93:1051-1052.
Mitchell BM, Dorrance AM, Webb RC. Phenylalanine improves vasodilation and blood pressure in GTPCH inhibition-induced hypertensive rats. J Cardiovasc Pharmacol 2004;43:758-763.
Mitchell BM, Dorrance AM, Ergul A, Webb RC. Sepiapterin decreases vasorelaxation in NOS inhibition-induced hypertension. J Cardiovasc Pharmacol 2004;43:93-98.
Mitchell BM, Dorrance AM, Mack EA, Webb RC. Glucocorticoids decrease GTP cyclohydrolase and tetrahydrobiopterin-dependent vasorelaxation through glucocorticoid receptors. J Cardiovasc Pharmacol 2004;43:8-13.
Mitchell BM, Dorrance AM, Webb RC. GTP cyclohydrolase 1 inhibition attenuates vasodilation and increases blood pressure in rats. Am J Physiol Heart Circ Physiol 2003;285:2165-2170.
Mitchell BM, Dorrance AM, Webb RC. GTP cyclohydrolase 1 down-regulation contributes to glucocorticoid hypertension in rats. Hypertension 2003;41:669-674.
