In recent years, it has become apparent that both innate and adaptive immunity contribute to the genesis of hypertension. We have discovered a novel mechanism that underlies activation of adaptive immunity in hypertension, involving the formation of isolevuglandins (isoLGs) in dendritic cells (DCs) and other antigen presenting cells. These lipid oxidation products adduct to proteins, resulting in formation of neoantigens that are processed and presented by major histocompatibility complexes (MHCs). IsoLG-modified proteins are increased in DCs of both mice and humans with hypertension and drive proliferation of subsets of T cells, particularly CD8+ T cells. In this research program, we are examining mechanisms responsible for formation of isoLGs in DCs. We have evidence that isoLGs are formed as a result of both NADPH oxidase activation and by reactive oxygen species generated by the mitochondria in DCs. Using unique mice we have made we are defining potential immunogenic peptides presented in MHC class 1 and determining if there are different peptides derived from mitochondria versus non-mitochondrial sources. Mass spectroscopy will also be employed to determine if similar isoLG modified peptides are presented by monocytes of humans with hypertension. In parallel studies performed in collaboration with Dr. Simon Mallal, the director of the Translational Immunology Core at Vanderbilt, we are characterizing the alpha and beta chain sequences of T cell receptors (TCR? and TCR?) in activated T cells of both mice and humans using single cell sequencing. This will allow us to produce surrogate T cells (transfectomas) that can be used to determine their responsiveness to isoLG-modified proteins and peptides presented in MHC class 1 of hypertensive mice. We have recently shown that hypertensive humans have a striking increase in circulating memory T cells that produce IL-17A and IFN-? compared to matched controls. Data from single cell sequencing will identify the TCR? and TCR? of these cells and to produce transfectomas expressing these sequences and to determine if they are also responsive to isoLG modified proteins presented in the context of APCs from the same individual. Identifying specific neoantigens in hypertension will provide an enormous advance in understanding this disease. These could serve as biomarkers of disease severity and be used to detect pathogenic T cells in hypertension. Ultimately immunization approaches could be employed to treat or prevent hypertension. Specific therapies to reduce isoLG formation have proven effective in experimental models and have substantial promise for treatment of human hypertension.
High blood pressure is an enormous health care burden in the United States, affecting one in three adults. It is a major cause of stroke, heart attack and kidney disease and despite this, the causes of hypertension remain poorly understood and treatment is not always successful. In our proposed studies, we will further define the inflammation that causes hypertension and develop new strategies to prevent this.
|Pandey, Arvind K; Singhi, Eric K; Arroyo, Juan Pablo et al. (2018) Mechanisms of VEGF (Vascular Endothelial Growth Factor) Inhibitor-Associated Hypertension and Vascular Disease. Hypertension 71:e1-e8|
|Patrick, David M; Harrison, David G (2018) Nocturnal noise knocks NOS by Nox: mechanisms underlying cardiovascular dysfunction in response to noise pollution. Eur Heart J 39:3540-3542|
|Loperena, Roxana; Van Beusecum, Justin P; Itani, Hana A et al. (2018) Hypertension and increased endothelial mechanical stretch promote monocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide. Cardiovasc Res 114:1547-1563|
|Norlander, Allison E; Madhur, Meena S; Harrison, David G (2018) The immunology of hypertension. J Exp Med 215:21-33|
|Gillis, Ellen E; Brinson, Krystal N; Rafikova, Olga et al. (2018) Oxidative stress induces BH4 deficiency in male, but not female, SHR. Biosci Rep 38:|
|Tran, Anh Nhat; Walker, Kiera; Harrison, David G et al. (2018) Reactive species balance via GTP cyclohydrolase I regulates glioblastoma growth and tumor initiating cell maintenance. Neuro Oncol 20:1055-1067|
|Van Beusecum, Justin P; Harrison, David G (2018) The nerve of the spleen! Causing hypertension by placental growth factor. Cardiovasc Res 114:356-357|