Eric Swanson

Introduction. Hypertension (HTN) is the leading cause of stroke, disease burden and death worldwide (1) In the United States, it affects 46% of adults and it is estimated that 13-17% of adults with HTN have uncontrolled or resistant HTN (1).  Due to the underlying heterogeneity in the pathogenesis of HTN there is a need for the development of new treatments (1).  Much of the current research focuses on the renin-angiotensin-aldosterone system (RAAS) with several recent studies uncovering a novel role of the ubiquitous enzyme Tissue Transglutaminase 2 (TG2) directly linking inflammatory cytokines to the generation of HTN (2-6).  The mechanism to which TG2 accomplishes this is through TG2 catalyzed post-translation modifications (PTM) of the angiotensin receptor type 1 (AT1R) enhancing the effect of the RAAS (4-6).  With a better understanding of this mechanism, these studies could provide insight into the generation of new antihypertensive therapies (7).  Methods. Researchers experimentally induced HTN in a mouse model using the proinflammatory cytokine LIGHT (TNFSF14) (2,3).  This model was then co-treated with cystamine or ERW1041E, which are specific TG2-inhibitors, and used tail cuff plethysmography to analyze blood pressure (6).  Relative AT1R levels and AT1R/-arrestin ratio levels in the mice kidneys were then analyzed via Western blots (6). Researchers then explored the functional consequences of LIGHT-induced TG2 catalyzed PTM in AT1R signaling by analyzing ANG-II-AT1R downstream calcium response using AT1R-NFAT-luciferase reporter cells with or without LIGHT (6). Results. These studies found that the expected increase in LIGHT-induced blood pressure was significantly ameliorated in models in which TG2’s function was inhibited (p < 0.05) (2,3,6).  TG2 inhibition also resulted in significantly decreased AT1R accumulation in response to LIGHT (p < 0.05) (4,6).  In addition, it was found that TG2 induced PTM of the AT1R resulted in significantly abrogated arrestin binding (p < 0.05) and that this PTM was repressed in either ERW1041E treatment or TG2 gene ablation (6).  Lastly, results showed significantly higher calcium response following ANG-II stimulation in the presence of LIGHT and that follow up inhibition of TG2 prevented the increase in ANG-II responsiveness (6).  Conclusions. TG2 mediated PTM upon the AT1R under LIGHT proinflammatory signaling leads to increased AT1R accumulation in the kidney, decreased B-arrestin-AT1R binding which leads to decreased AT1R degradation, and enhanced downstream ANG II-AT1R calcium signaling resulting in increased ANG II sensitivity (6).  Taken together, these findings unmask the previously unrecognized role of TG2 in the generation of HTN and lay the groundwork for future novel antihypertensive medications that exploit this mechanism.

1. Paul K. Whelton, Robert M. Carey, Wilbert S. Aronow, Donald E. Casey, Karen J. Collins, Cheryl Dennison Himmelfarb, Sondra M. DePalma, Samuel Gidding, Kenneth A. Jamerson, Daniel W. Jones, Eric J. MacLaughlin, Paul Muntner, Bruce Ovbiagele, Sidney C. Smith, Crystal C. Spencer, Randall S. Stafford, Sandra J. Taler, Randal J. Thomas, Kim A. Williams, Jeff D. Williamson, Jackson T. Wright, 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults, Journal of the American College of Cardiology, Volume 71, Issue 19, May 2018.
2. Chen Liu , Wei Wang , Nicholas Parchim , Roxanna A. Irani , Sean C. Blackwell , Baha Sibai , Jianping Jin , Rodney E. Kellems , and Yang Xia, Tissue Transglutaminase Contributes to the Pathogenesis of Preeclampsia and Stabilizes Placental Angiotensin Receptor Type 1 by Ubiquitination-Preventing Isopeptide Modification, Hypertension, Vol 63, Issue 2, February 2014.
3. Engholm M, Eftekhari A, Chwatko G, Bald E, Mulvany M.J., Effect of Cystamine on Blood Pressure and Vascular Characteristics in Spontaneously Hypertensive Rats, Journal of Vascular Research, Volume 48 Pages 476-484, October 2011.
4. Chen Liu, Renna Luo, Serra E. Elliott, Wei Wang, Nicholas F. Parchim, Takayuki Iriyama, Patrick S. Daugherty, Sean C. Blackwell, Baha M. Sibai, Rodney E. Kellems, Yang Xia, Elevated Transglutaminase Activity Triggers Angiotensin Receptor Activating Autoantibody Production and Pathophysiology of Preeclampsia, Journal of the American Heart Association, Volume 4, Issue 12, 23 December 2015.
5. Renna Luo, Chen Liu, Serra E. Elliott, Wei Wang, Nicholas Parchim, Takayuki Iriyama, Patrick S. Daugherty, Lijian Tao, Holger K. Eltzschig, Sean C. Blackwell, Baha M. Sibai, Rodney E. Kellems, Yang Xia, Transglutaminase is a Critical Link Between Inflammation and Hypertension, Journal of the American Heart Association, Vol 5, Issue 7, 06 July 2016.
6. Liu C, Luo R, Wang W, et al. Tissue Transglutaminase-Mediated AT1 Receptor Sensitization Underlies Pro-Inflammatory Cytokine LIGHT-Induced Hypertension. American Journal of Hypertension. 2019;32(5):476–485.
7. Chen Liu, Rodney E. Kellems, Yang Xia; Inflammation, Autoimmunity, and Hypertension: The Essential Role of Tissue Transglutaminase, American Journal of Hypertension, Volume 30, Issue 8, 1 August 2017, Pages 756–764.