Profile

Our laboratory has been focused on understanding how inflammation, and in particular, the adaptive immune response contributes to hypertension. Several years ago, we found that T cells are essential for the development of hypertension. We have shown that various hypertensive stimuli, including angiotensin II, norepinephrine and DOCA-salt cause activation of T cells and leads to their accumulation in the perivascular fat and kidneys. Our data indicate that T cell-derived cytokines such as IL-17 and TNF-a enhance vasoconstriction and sodium retention, leading to the hypertensive phenotype. Central signals derived from the circumventricular organs contribute to T cell activation, and manipulation of signals from this region affect T cell activation and the eventual elevation in blood pressure caused by angiotensin II. Our current studies are directed toward understanding the specific subtypes of T cells involved in hypertension. We are attempting to understand mechanisms involved in T cell activation in response to hypertensive stimuli. 

We have recently discovered a novel post-translational protein modification which occurs in hypertension. We found that isoketals, or gamma-ketoaldehydes which are oxidized products of fatty acids, adduct to self proteins in dendritic cells, and act as neoantigens in this disease. We are currently trying to understand what signals lead to isoketal formation, determine the modified proteins and determine if a select population of T cells respond to isoketal adducted peptides when they are presented in MHC. 

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Macrophages in vascular inflammation--From atherosclerosis to vasculitis. Shirai T, Hilhorst M, Harrison DG, Goronzy JJ, Weyand CM (2015) Autoimmunity 48(3): 139-51
    › Primary publication · 25811915 (PubMed) · PMC4606880 (PubMed Central)
  2. Phage-display-guided nanocarrier targeting to atheroprone vasculature. Hofmeister LH, Lee SH, Norlander AE, Montaniel KR, Chen W, Harrison DG, Sung HJ (2015) ACS Nano 9(4): 4435-46
    › Primary publication · 25768046 (PubMed) · PMC4654777 (PubMed Central)
  3. Inflammation, immunity, and hypertensive end-organ damage. McMaster WG, Kirabo A, Madhur MS, Harrison DG (2015) Circ Res 116(6): 1022-33
    › Primary publication · 25767287 (PubMed) · PMC4535695 (PubMed Central)
  4. Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation. Saleh MA, McMaster WG, Wu J, Norlander AE, Funt SA, Thabet SR, Kirabo A, Xiao L, Chen W, Itani HA, Michell D, Huan T, Zhang Y, Takaki S, Titze J, Levy D, Harrison DG, Madhur MS (2015) J Clin Invest 125(3): 1189-202
    › Primary publication · 25664851 (PubMed) · PMC4362266 (PubMed Central)
  5. Renal transporter activation during angiotensin-II hypertension is blunted in interferon-γ-/- and interleukin-17A-/- mice. Kamat NV, Thabet SR, Xiao L, Saleh MA, Kirabo A, Madhur MS, Delpire E, Harrison DG, McDonough AA (2015) Hypertension 65(3): 569-76
    › Primary publication · 25601932 (PubMed) · PMC4326622 (PubMed Central)
  6. GTP cyclohydrolase I gene polymorphisms are associated with endothelial dysfunction and oxidative stress in patients with type 2 diabetes mellitus. Wolkow PP, Kosiniak-Kamysz W, Osmenda G, Wilk G, Bujak-Gizycka B, Ignacak A, Kanitkar M, Walus-Miarka M, Harrison DG, Korbut R, Malecki MT, Guzik TJ (2014) PLoS One 9(11): e108587
    › Primary publication · 25369080 (PubMed) · PMC4219671 (PubMed Central)
  7. Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension. Nozik-Grayck E, Woods C, Taylor JM, Benninger RK, Johnson RD, Villegas LR, Stenmark KR, Harrison DG, Majka SM, Irwin D, Farrow KN (2014) Am J Physiol Lung Cell Mol Physiol 307(11): L868-76
    › Primary publication · 25326578 (PubMed) · PMC4254965 (PubMed Central)
  8. Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Trott DW, Thabet SR, Kirabo A, Saleh MA, Itani H, Norlander AE, Wu J, Goldstein A, Arendshorst WJ, Madhur MS, Chen W, Li CI, Shyr Y, Harrison DG (2014) Hypertension 64(5): 1108-15
    › Primary publication · 25259750 (PubMed) · PMC4191997 (PubMed Central)
  9. DC isoketal-modified proteins activate T cells and promote hypertension. Kirabo A, Fontana V, de Faria AP, Loperena R, Galindo CL, Wu J, Bikineyeva AT, Dikalov S, Xiao L, Chen W, Saleh MA, Trott DW, Itani HA, Vinh A, Amarnath V, Amarnath K, Guzik TJ, Bernstein KE, Shen XZ, Shyr Y, Chen SC, Mernaugh RL, Laffer CL, Elijovich F, Davies SS, Moreno H, Madhur MS, Roberts J, Harrison DG (2014) J Clin Invest 124(10): 4642-56
    › Primary publication · 25244096 (PubMed) · PMC4220659 (PubMed Central)
  10. Basic science: Pathophysiology: oxidative stress. Harrison DG (2014) J Am Soc Hypertens 8(8): 601-3
    › Primary publication · 25151322 (PubMed) · PMC4300202 (PubMed Central)
  11. The immune system in hypertension. Trott DW, Harrison DG (2014) Adv Physiol Educ 38(1): 20-4
    › Primary publication · 24585465 (PubMed) · PMC4459918 (PubMed Central)
  12. Role of vascular oxidative stress in obesity and metabolic syndrome. Youn JY, Siu KL, Lob HE, Itani H, Harrison DG, Cai H (2014) Diabetes 63(7): 2344-55
    › Primary publication · 24550188 (PubMed) · PMC4066332 (PubMed Central)
  13. From ST segments to endothelial pathophysiology: hypercholesterolemia and endothelial superoxide production. Harrison DG (2014) J Clin Invest 124(2): 473-5
    › Primary publication · 24487641 (PubMed) · PMC3904616 (PubMed Central)
  14. Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L, Madhur MS, Chen W, Harrison DG (2014) Circ Res 114(4): 616-25
    › Primary publication · 24347665 (PubMed) · PMC4186716 (PubMed Central)
  15. Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension. Dikalov SI, Nazarewicz RR, Bikineyeva A, Hilenski L, Lassègue B, Griendling KK, Harrison DG, Dikalova AE (2014) Antioxid Redox Signal 20(2): 281-94
    › Primary publication · 24053613 (PubMed) · PMC3887459 (PubMed Central)
  16. A common functional promoter variant links CNR1 gene expression to HDL cholesterol level. Feng Q, Vickers KC, Anderson MP, Levin MG, Chen W, Harrison DG, Wilke RA (2013) Nat Commun : 1973
    › Primary publication · 23748922 (PubMed) · PMC3873874 (PubMed Central)
  17. Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. Wiig H, Schröder A, Neuhofer W, Jantsch J, Kopp C, Karlsen TV, Boschmann M, Goss J, Bry M, Rakova N, Dahlmann A, Brenner S, Tenstad O, Nurmi H, Mervaala E, Wagner H, Beck FX, Müller DN, Kerjaschki D, Luft FC, Harrison DG, Alitalo K, Titze J (2013) J Clin Invest 123(7): 2803-15
    › Primary publication · 23722907 (PubMed) · PMC3696542 (PubMed Central)
  18. Senescent T cells and hypertension: new ideas about old cells. Madhur MS, Harrison DG (2013) Hypertension 62(1): 13-5
    › Primary publication · 23716580 (PubMed) · PMC3734939 (PubMed Central)
  19. Dysfunctional resident lung mesenchymal stem cells contribute to pulmonary microvascular remodeling. Chow K, Fessel JP, Kaoriihida-Stansbury , Schmidt EP, Gaskill C, Alvarez D, Graham B, Harrison DG, Wagner DH, Nozik-Grayck E, West JD, Klemm DJ, Majka SM (2013) Pulm Circ 3(1): 31-49
    › Primary publication · 23662173 (PubMed) · PMC3641738 (PubMed Central)
  20. Knock, knock: who's there?: Nox1. Itani HA, Dikalov S, Harrison DG (2013) Circulation 127(18): 1850-2
    › Primary publication · 23564667 (PubMed) · PMC3909710 (PubMed Central)
  21. Nitric oxide reduces Cl⁻ absorption in the mouse cortical collecting duct through an ENaC-dependent mechanism. Pech V, Thumova M, Dikalov SI, Hummler E, Rossier BC, Harrison DG, Wall SM (2013) Am J Physiol Renal Physiol 304(11): F1390-7
    › Primary publication · 23515718 (PubMed) · PMC3680692 (PubMed Central)
  22. The mosaic theory revisited: common molecular mechanisms coordinating diverse organ and cellular events in hypertension. Harrison DG (2013) J Am Soc Hypertens 7(1): 68-74
    › Primary publication · 23321405 (PubMed) · PMC3646628 (PubMed Central)
  23. Studies of the T-cell angiotensin receptor using cre-lox technology: an unan-T-cellpated result. Harrison DG, Guzik TJ (2012) Circ Res 110(12): 1543-5
    › Primary publication · 22679135 (PubMed)