Atherosclerotic cardiovascular disease is a major killer in America, accounting for 40% of all deaths. Vascular endothelial cell (EC) function promotes cardiovascular health by providing normal barrier function and adaptive defense against oxidative stress and vascular aging and atherosclerosis. Failure of these key endothelial functions leads to critical vascular diseases, and atherosclerosis is the most common and devastating of these. Epigenetic mechanisms have been shown to maintain normal EC homeostasis, but the role and activity of these mechanisms in atherosclerotic vessels remain poorly understood. Histone deacetylase 2 (HDAC2) has emerged from our work as a critical gene regulator that promotes EC redox balance and normal vascular reactivity and responsiveness. Our data document a dramatic fall in HDAC2 levels in EC and mouse aortas after oxidative injury, and implicate post-translational modification via NEDDylation as the cause of HDAC2 degradation with this oxidative insult. We have also shown that HDAC2 enhances the transcription of an enzyme that preserves EC function by preventing senescence and the loss of barrier permeability - ZMPSTE24 (Zinc Metallopeptidase STE24). Our data also show that ZMPSTE24 levels are reduced in EC that are exposed to OxLDL. Moreover, a reduction in ZMPSTE24 causes a dramatic reciprocal increase in the abundance of endothelial prelamin A in isolated aortas from atherosclerotic and aged mice, while mutations in ZMPSTE24 pathways lead to premature aging (progeria) syndromes and profoundly accelerated and malignant atherosclerosis. We have developed state-of-the-art tools and mouse models to interrogate our overarching hypothesis that the following series of events sparks accelerated atherogenesis: Oxidative injury attenuates HDAC2 in EC, resulting in decreased ZMPSTE24; This paucity of ZMPSTE24 results in toxic accumulation of the nuclear scaffold protein prelamin A; Excess prelamin A promotes EC senescence, compromises EC barrier integrity, and atherosclerosis. In the first Aim, we will define mechanisms by which HDAC2 regulates ZMPSTE24 transcription and expression in EC, and determine the role of ZMPSTE24 in EC homeostasis.
Aim two focuses on the process of accelerated HDAC2 degradation after oxidative injury, and the specific ubiquitin ligases that mediate Nedd8 modification of HDAC2, and the effects of neddylation inhibitor MLN4924 in endothelial dysfunction and atherogenesis in vivo.
The third Aim will define the specific impact of HDAC2 expression on endothelial senescence, barrier function, and atheroma formation. These studies will produce strategies for increasing HDAC2 abundance, supporting endothelial function, and devising novel components for a therapeutic regimen preventing or slowing of atherosclerosis.

Public Health Relevance

High levels of cholesterol and related circulating lipids lead to the progression of coronary artery and other atherosclerotic vascular diseases by reducing the production of protective molecules released by the lining of the blood vessels (the endothelium), and by increasing the availability of substances that are damaging. We have identified an enzyme that is made in the endothelium that prevents injury to the lining of blood vessels and that may slow or prevent atherosclerosis. In this proposal we will study how this enzyme has its protective effects on blood vessels and determine whether understanding this enzyme may yield new treatments for blood vessel diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56HL139736-01A1
Application #
10002625
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2019-09-15
Project End
2020-08-31
Budget Start
2019-09-15
Budget End
2020-08-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205