PROGRAM DIRECTOR, WEBB The integrating theme and unifying hypothesis of this program project centers on the role played by damage- associated-molecular patterns (DAMPs) in hypertension. DAMPs are alarm signals generated from injured host cells, damaged tissues or metabolic stress and are recognized by the innate immune system. We hypothesize that sustained activation of the innate immune system in hypertension is maladaptive, leading to activation of circulating neutrophils and monocytes in the peripheral circulation, which home to the vasculature, and cause increased tissue destruction and low-grade inflammation. These inflammatory events contribute to increased vasoconstriction, vascular remodeling, and renal injury that occur under the action of initiating factors to increase blood pressure. Project 1 will test the hypothesis that in hypertension, exaggerated apoptosis and necrosis in the vascular wall give rise to mitochondrial DNA (mtDNA), a DAMP that activates Toll-like receptor 9 (TLR9) causing vascular inflammation, vasoconstriction and endothelial dysfunction. In Project 2, it is hypothesized that cell death induces high mobility group box 1 (HMGB1) release and TLR4 activation resulting in dentritic cell (DC) and T cell activation and increases in blood pressure in both sexes. However, due to a sex difference in the type of cell death, the molecular pathway driving immune-based hypertension in females favors greater T regulatory cell (Treg) formation. This hypothesis predicts that necrosis results in greater HMGB1 release and TLR4 activation in males leading to myeloid DC activation of Th17 cells and increases in blood pressure and end-organ damage relative to females, while greater apoptosis in females limits HMGB1 release and activates plasmacytoid DC to increase Treg formation limiting increases in blood pressure and injury relative to males. Project 3 tests the hypothesis that high circulating DAMPs stimulate inappropriate nitric oxide (NO) production by vasa recta (VR) endothelial cells in low sheer states. This NO production is detrimental as it inhibits spontaneous rhythmic contractions of VR pericytes that normally act to prevent red blood cell aggregations under these conditions. RBC occlusion of the VR then leads to rarefaction of the surrounding medullary vasculature, impaired pressure-natriuresis and hypertension. These conceptually unique approaches, combined with novel technological tools will advance our understanding of the molecular and physiological mechanisms underlying the initiation of vascular injury and end organ damage of hypertension. All projects will use the spontaneously hypertensive rat as an animal model. This highly integrative and collaborative approach of the three component projects is supported by an Administrative Core (Core A), the Animal Use and Instrumentation Core (Core B) and the Bioinflammation Core (Core C).

Public Health Relevance

PROGRAM NARRATIVE PROGRAM DIRECTOR, WEBB The last decade has shown an increase in the understanding of inflammation and its mediators in cardiovascular and renal biology; thus, the role of inflammation in hypertension is now a matter of intense investigation. Basic science and translational studies have proved that elements belonging to both innate and adaptive immunity are involved in the development and progression of hypertension and the related end organ injury. Therapies targeting the pathophysiological cause of hypertension will undoubtedly improve blood pressure control rates and prevent premature death from cardiovascular disease. Thus, the studies proposed in this program project offer promise for the discovery of new therapeutic targets to ameliorate vascular and renal inflammation related to activation of the innate immune response, which could lead to improved outcome in cardiovascular disease in humans.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Varagic, Jasmina
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Augusta University
Schools of Medicine
United States
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Komic, Amel; Martinez-Quinones, Patricia; McCarthy, Cameron G et al. (2018) Increase in soluble protein oligomers triggers the innate immune system promoting inflammation and vascular dysfunction in the pathogenesis of sepsis. Clin Sci (Lond) 132:1433-1438
Gonçalves, Tiago Tomazini; Lazaro, Carolina M; De Mateo, Fernanda G et al. (2018) Effects of glucosyl-hesperidin and physical training on body weight, plasma lipids, oxidative status and vascular reactivity of rats fed with high-fat diet. Diabetes Metab Syndr Obes 11:321-332
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Klee, Nicole S; McCarthy, Cameron G; Lewis, Steven et al. (2018) Urothelial Senescence in the Pathophysiology of Diabetic Bladder Dysfunction-A Novel Hypothesis. Front Surg 5:72
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Taylor, Lia E; Gillis, Ellen E; Musall, Jacqueline B et al. (2018) High Fat Diet Induced Hypertension is Associated with a Pro-Inflammatory T Cell Profile in Male and Female Dahl Salt Sensitive Rats. Am J Physiol Heart Circ Physiol :
Wenceslau, Camilla F; McCarthy, Cameron G; Webb, R Clinton (2018) To Be, or Nox to Be, Endoplasmic Reticulum Stress in Hypertension. Hypertension 72:59-60
McCarthy, Cameron G; Wenceslau, Camilla F (2018) Adopting an Orphan: How Could GRP35 Contribute to Angiotensin II-Dependent Hypertension? Am J Hypertens 31:973-975

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