This proposal describes a five year training program to develop a career in academic cardiovascular medicine. The applicant will aim to obtain the credentials and funding support necessary to achieve independence as an investigator, with the long term career goals to provide insights into novel signaling processes that are essential to vascular physiology and pathophysiology. The goals of the applicant over the next five years will be to master additional experimental techniques, enhance knowledge of molecular biological concepts, and develop administrative skills necessary to conduct independent research. With the guidance from his mentor, Dr. Thomas Quertermous, as well as carefully selected panel of Advisory Committee of senior investigators, the applicant will receive sufficient support to achieve these goals. Project Description: G-protein coupled receptor (GPCR) signaling plays an important role in regulation of cardiovascular pathologic processes. APJ is a GPCR with a 31% homology to the angiotensin II type 1 receptor. Its ligand apelin is a potent inotrope with vasodilatory properties that are in part mediated by nitric oxide. Our recent findings have demonstrated inhibition of angiotensin II signaling by the apelin-APJ pathway, leading to near complete abrogation of angiotensin ll-mediated atherosclerosis. In addition, we have identified high expression of apelin and APJ in the pulmonary vasculature. Significant modulation of apelin and APJ expression also occurs in patients and animal models of pulmonary hypertension, suggesting a yet to be defined role of apelin in the pulmonary vasculature. Moreover, our work with the APJ deficient mice demonstrate significantly elevated pulmonary artery pressures, suggesting an important role in the pulmonary vascular homeostasis. In this proposal we seek to further define the role of apelin signaling in both systemic and pulmonary vasculature. We hypothesize that the apelin-APJ pathway plays a critical role in these structures, and that modulation of apelin signaling may serve a role in inhibiting disease processes involving the vasculature such as atherosclerosis and pulmonary hypertension.
Our specific aims i nclude: 1) characterization of the apelin-APJ signaling pathway in mouse model of atherosclerosis, 2) determining the role of the apelin-APJ signaling pathway in pulmonary vascular wall disease, and 3) characterization of the crosstalk between the apelin-APJ pathway and angiotensin II pathway. The proposed studies will extend our understanding of the apelin-APJ pathway, and provide further insights into the potential therapeutic benefits of this pathway in vascular wall disease.

Public Health Relevance

Apelin is a recently discovered signaling peptide. Our recent data demonstrate a potent protective role of apelin signaling against pathologic stress that mediates vascular wall disease. Elucidating the role of apelin in vascular wall signaling may lead to novel therapeutic strategies to target disease processes such as atherosclerosis and pulmonary hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-O (M1))
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Commarato, Michael
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Hwangbo, Cheol; Wu, Jingxia; Papangeli, Irinna et al. (2017) Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects. Sci Transl Med 9:
Hwangbo, Cheol; Lee, Heon-Woo; Kang, Hyeseon et al. (2017) Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension. Circulation 135:2288-2298
Papangeli, Irinna; Kim, Jongmin; Maier, Inna et al. (2016) MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation. Nat Commun 7:11268
Papangeli, Irinna; Sharma, Bikram; Chun, Hyung J (2015) Letter by Papangeli et al Regarding Article, ""The ERG-APLNR Axis Controls Pulmonary Venule Endothelial Proliferation in Pulmonary Veno-Occlusive Disease"". Circulation 132:e16
Kim, Jongmin; Hwangbo, Cheol; Hu, Xiaoyue et al. (2015) Restoration of impaired endothelial myocyte enhancer factor 2 function rescues pulmonary arterial hypertension. Circulation 131:190-9
Kim, Jun-Dae; Kang, Yujung; Kim, Jongmin et al. (2014) Essential role of Apelin signaling during lymphatic development in zebrafish. Arterioscler Thromb Vasc Biol 34:338-45
Mehrotra, Devi; Wu, Jingxia; Papangeli, Irinna et al. (2014) Endothelium as a gatekeeper of fatty acid transport. Trends Endocrinol Metab 25:99-106
Kang, Yujung; Kim, Jongmin; Anderson, Joshua P et al. (2013) Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development. Circ Res 113:22-31
Kim, Jongmin; Kang, Yujung; Kojima, Yoko et al. (2013) An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med 19:74-82
Jane-Wit, Daniel; Chun, Hyung J (2012) Mechanisms of dysfunction in senescent pulmonary endothelium. J Gerontol A Biol Sci Med Sci 67:236-41

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