Our lab has been studying the role if specific phosphorylation site, serine 1179 in regulating eNOS function and that the protein kinase Akt1 is necessary for post-natal angiogenesis in response to hindlimb ischemia or to exogenous administration of vascular endothelial growth factor (VEGF). In this competitive renewal, we will examine the role of eNOS phosphorylation on S1176 in macro- and micro-vascular functions of endothelial derived NO, namely atheroprotection and angiogenesis, respectively. Thus, we hypothesize that the phosphorylation of eNOS governs the production of NO to regulate macrovascular (atheroprotection) and microvascular (angiogenesis) functions in the cardiovascular system. To test these hypotheses, we propose the following Specific Aims: 1.Determine the mechanisms of why the loss of Akt1 promotes coronary atherogenesis. We will explore potential mechanisms in vitro in isolated macrophages and vascular cells, in vivo by bone marrow transplantation experiments and by breeding eNOS phosphomutant mice to the ApoE/Akt1 null background;2. Dissect the role of endothelial specific Akt1 regulating macrovascular (atherogenesis) and microvascular (angiogenesis) function by conditional deletion of Akt1 in endothelial cells;3 Decipher the importance of eNOS phosphorylation on serine 1176 using knockin mice expressing either constitutively active (S1176D eNOS) or less active eNOS (S1176A eNOS). The importance of eNOS as a key Akt substrate will be tested in vitro and in several postnatal models of angiogenesis in mice replete or deficient in Akt1. Collectively, this work will facilitate our understanding of the importance of eNOS phosphorylation in atherogenesis and angiogenesis and provide insights into the molecular machinery required for eNOS regulation using a multi-disciplinary approach.

Public Health Relevance

This research is relevant to public health since endothelial dysfunction is a common manifestation of most cardiovascular diseases. Our research has discovered the major mechanisms of how the endothelium control blood flow and atherogenesis. Research supported by this grant may help identify new drugs that reduce heart disease and improve the quality of life of people suffering with cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064793-11
Application #
7765486
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Wood, Katherine
Project Start
2000-03-07
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
11
Fiscal Year
2010
Total Cost
$413,750
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Hoffmann, Reuben; Grabi?ska, Kariona; Guan, Ziqiang et al. (2017) Long-Chain Polyprenols Promote Spore Wall Formation in Saccharomyces cerevisiae. Genetics 207:1371-1386
Grabi?ska, Kariona A; Edani, Ban H; Park, Eon Joo et al. (2017) A conserved C-terminal RXG motif in the NgBR subunit of cis-prenyltransferase is critical for prenyltransferase activity. J Biol Chem 292:17351-17361
Kuo, Andrew; Lee, Monica Y; Sessa, William C (2017) Lipid Droplet Biogenesis and Function in the Endothelium. Circ Res 120:1289-1297
Kraehling, Jan R; Sessa, William C (2017) Contemporary Approaches to Modulating the Nitric Oxide-cGMP Pathway in Cardiovascular Disease. Circ Res 120:1174-1182
Luciano, Amelia K; Santana, Jeans M; Velazquez, Heino et al. (2017) Akt1 Controls the Timing and Amplitude of Vascular Circadian Gene Expression. J Biol Rhythms 32:212-221
Park, Eon Joo; Grabi?ska, Kariona A; Guan, Ziqiang et al. (2016) NgBR is essential for endothelial cell glycosylation and vascular development. EMBO Rep 17:167-77
Kraehling, Jan R; Hao, Zhengrong; Lee, Monica Y et al. (2016) Uncoupling Caveolae From Intracellular Signaling In Vivo. Circ Res 118:48-55
Marin, Ethan P; Jozsef, Levente; Di Lorenzo, Annarita et al. (2016) The Protein Acyl Transferase ZDHHC21 Modulates ?1 Adrenergic Receptor Function and Regulates Hemodynamics. Arterioscler Thromb Vasc Biol 36:370-9
Grabi?ska, Kariona A; Park, Eon Joo; Sessa, William C (2016) cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases. J Biol Chem 291:18582-90
Chamorro-Jorganes, Aránzazu; Lee, Monica Y; Araldi, Elisa et al. (2016) VEGF-Induced Expression of miR-17-92 Cluster in Endothelial Cells Is Mediated by ERK/ELK1 Activation and Regulates Angiogenesis. Circ Res 118:38-47

Showing the most recent 10 out of 105 publications