P1, WEBB Toll-like receptor 9 activation by mitochondrial DNA causes vascular injury in hypertension Hypertension affects over 75 million U.S. adults and plays a major role in the end organ damage commonly seen with cardiovascular diseases, including stroke, coronary artery disease, and ischemic nephropathy. Our proposal provides a new paradigm whereby activation of the innate immune system via mitochondrial DNA (mtDNA) leads to increased vasoconstriction, reduced vasodilation and vascular remodeling in hypertension. Understanding this mechanism may assist in the development of new drugs that target the immune system to treat vascular dysfunction and prevent the progression of hypertension. The research will be guided by the novel hypothesis that in hypertension, exaggerated vascular and tissue cell death give rise to mtDNA that trigger the innate immune response via Toll-like receptor 9 (TLR9) causing vascular inflammation, vasoconstriction, endothelial dysfunction and vascular remodeling. A rat model of hypertension [spontaneously hypertensive rat (SHR)] will be used and we will test our hypothesis by accomplishing three specific aims: 1) test the hypothesis that pharmacological inhibition of cell necrosis attenuates the development of vascular dysfunction in hypertension; 2) test the hypothesis that activation of TLR9 signaling causes endothelial dysfunction, potentiates vasoconstriction and contributes to arterial stiffening; and 3) test the hypothesis that mtDNA contributes to the development and maintenance of hypertension. The proposed studies, integrating physiological, pharmacological, biochemical, molecular and cellular techniques, will help to better understand the effects of blood pressure on vascular function, as well as the contribution of abnormal TLR9 activation to vascular dysfunction characteristic of hypertension.

Public Health Relevance

P1, WEBB Our proposal provides a new paradigm whereby activation of the innate immune system via mitochondrial DNA (mtDNA) leads to increased vasoconstriction, reduced vasodilation and vascular remodeling in hypertension. Understanding this mechanism may assist in the development of new drugs that target the immune system to treat vascular dysfunction and prevent the progression of hypertension. The research will be guided by the hypothesis that in hypertension, exaggerated vascular and tissue cell death give rise to mtDNA that trigger the innate immune response via Toll-like receptor 9 (TLR9) causing vascular dysfunction in a rat model of hypertension [spontaneously hypertensive rat (SHR)].

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL134604-05
Application #
10094229
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Varagic, Jasmina
Project Start
2017-02-01
Project End
2022-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
5
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Augusta University
Department
Type
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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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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
Wynne, Brandi M; McCarthy, Cameron G; Szasz, Theodora et al. (2018) Protein kinase C? deletion causes hypotension and decreased vascular contractility. J Hypertens 36:510-519

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