Angiotensin II (Ang II) plays a central role in the pathophysiology of vascular hypertrophy and endothelial dysfunction in hypertension, however very little is known regarding the cellular or molecular mechanisms that contribute to such vascular alterations in hypertension. Toll-like receptors (TLR) are type I transmembrane receptors that play a key role in innate immunity. Recent evidence suggests that, in addition to LPS, TLR4 signaling can be activated by endogenous factors produced during cell stress and/or injury. Our preliminary data indicate that TLR4 deficiency limits the development of Ang II-induced endothelial dysfunction. The mammalian target of rapamycin (mTOR;a member of the phosphoinositide 3-kinase-related kinase family of protein kinases) has recently been identified as an important regulator of cell growth and hypertrophy. Although mTOR has been implicated as playing an important role in cell growth and hypertrophy, the role of mTOR has not been previously examined in hypertension. Previous studies from our laboratory have implicated an important role for interleukin (IL)-6 and NAD(P)H oxidase in the endothelial dysfunction and vascular hypertrophy associated with Ang II-dependent hypertension. Our overarching hypothesis is that TLR4 and mTOR are key molecular mechanisms, vis-a-vis IL-6 and Nox-derived superoxide, that contribute to hypertension and hypertension-related vascular and microvascular sequelae.
Three Specific Aims will be addressed:
Aim 1 will test the hypothesis that TLR4 activation is an initial event that contributes to vascular hypertrophy and endothelial dysfunction in Ang II-dependent hypertension.
Aim 2 will test the hypothesis that mTOR activation downstream of TLR4 activation contributes to vascular hypertrophy and endothelial dysfunction in Ang II-dependent hypertension.
Aim 3 will test the hypothesis that IL-6 and NAD(P)H oxidase-derived superoxide serves as molecular links between TLR4 activation and downstream activation of mTOR in Ang II- dependent hypertension. The proposed studies are extremely novel and highly significant as they represent the first mechanistic examination of the roles of TLR4 and mTOR signaling in vascular and microvascular alterations that are clinically relevant to human hypertension. The studies also hold translational importance in hypertension as they will identify new molecular targets for therapeutic intervention.

Public Health Relevance

Hypertension is associated with an increased incidence of cardiovascular disease and events including carotid artery disease and stroke. Studies in this proposal are designed to examine the contribution and/or activation of specific components of the immune response to hypertension. The proposed studies are of clinical and translational importance as they are aimed at developing new therapeutic targets for which new treatment could be developed for hypertensive patients and improving public health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107632-03
Application #
8442817
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2011-04-15
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$355,810
Indirect Cost
$117,810
Name
University of Mississippi Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
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Didion, Sean P (2011) Tacrolimus-induced hypertension: what's endothelial and hematopoietic FKBP12 got to do with it? Hypertension 57:1058-60