Despite the recognized role of inflammation in cardiovascular diseases including atherosclerosis, this role may not be an initiating or essential mechanism in atherogenesis because current clinical practice is unsuccessful or has low efficiency if only using anti-inflammatory therapeutic strategy in treatment and prevention of cardiovascular diseases such as atherosclerosis. Endothelial dysfunction is the very early stage of many cardiovascular diseases including atherosclerosis. However, it remains unknown what mechanism can initiate endothelial dysfunction at early stages prior to or during inflammation. Recent studies have shown that Nlrp3 inflammasomes is a major intracellular molecular machinery to switch on the inflammatory response. Interestingly, our preliminary studies demonstrated that the formation and activation of Nlrp3 inflammasomes in endothelial cells were observed in response to danger factors including cholesterol crystal and visfatin (an injurious adipokine) and that some interesting early direct effects beyond inflammation were also shown to be induced by Nlrp3 inflammasome activation such as impaired endothelium-dependent vasodilation, enhanced vascular permeability or cell infiltration, and pathogenic homing or differentiation of endothelial progenitor cells. This may represent a novel pathogenic mechanism of inflammasome activation beyond inflammation. Thus, we hypothesize that beyond inflammation, activation of endothelial inflammasomes by endogenous danger signals directly induces endothelial dysfunction and vascular injury in coronary arteries. To test this hypothesis, we proposed 3 specific aims.
Aim 1 will determine whether Nlrp3 inflammasomes are formed and activated in response to danger factors such as cholesterol crystal and visfatin and which non-inflammatory effects are induced by activated Nlrp3 inflammasomes in addition to inflammatory response using coronary arterial ECs (CAECs) from Nlrp3-/- and Nlrp3+/+ mice.
Aim 2 will determine whether activated endothelial Nlrp3 inflammasomes contribute to coronary endothelial dysfunction and vascular injury in vivo independent of inflammation using Nlrp3-/- mice and their wild type littermates.
Aim 3 will explore how endothelial Nlrp3 inflammasomes are activated to produce coronary vascular injurious actions beyond inflammation and which inflammasome-activating pathway mainly produces the non-inflammatory effects using primary culture of CAECs and Nlrp3-/- mice and their littermates. The findings from this grant proposal will for the first time explore the non-inflammatory role of inflammasome in coronary endothelial dysfunction and vascular injury and define the early, initiating mechanisms mediating the response of CAECs to endogenous danger signals such as increased plasma cholesterol, cytokine or adipokines, which will provide new insights into the pathogenesis of vascular disease associated with endothelial dysfunction and microvascular injury.

Public Health Relevance

This grant application for the first time links a novel mechanism, namely, inflammasomes within cells in the inner layer of arteries to vascular injury and artery hardening. It will answer an important question, that is, how vascular injury and artery hardening start within cells at the very early stage of patient with cardiovascular disease and/or coronary risk factor such as hypertension, dyslipidemia, obesity, diabetes mellitus, or hyperhomocysteinemia. Such answer will help develop new strategies for treatment and prevention of vascular injury and artery hardening in these patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122769-03
Application #
9111962
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Olive, Michelle
Project Start
2014-09-22
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Houston
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204
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