Myocardial infarction is the leading cause of mortality and morbidity in the US. Following reperfusion, angiogenesis and restoration of microcirculation is a critical component in the recovery of normal cardiac function. Angiogenesis is also important for zebrafish heart regeneration. Much progress has been made towards understanding of the molecular mechanisms of angiogenesis, but the connection between metabolism and angiogenesis is less studied. My preliminary studies strongly suggest that cholesterol efflux from endothelial cells regulates angiogenesis. I found that angiogenesis in vitro and in embryonic zebrafish was regulated by ApoA-I binding protein (AIBP), a secreted protein identified in a screen of proteins that physically associate with ApoA-I. AIBP accelerated ABCG1-mediated cholesterol efflux from endothelial cells (EC) in vitro. Furthermore, AIBP controlled formation of segmental arteries (SeA) in embryonic zebrafish. Overexpression of AIBP inhibited SeA sprouting, while AIBP knockdown resulted in dysregulated SeA sprouting and branching. In my mentored K99 phase, I propose to test the hypothesis that secreted AIBP functions as a site-specific regulator of cholesterol efflux from EC and governs embryonic angiogenesis. First, I plan to demonstrate that AIBP-mediated, ABC transporters-dependent cholesterol efflux regulates embryonic angiogenesis in zebrafish. I found that the phenotype caused by the loss of AIBP was phenocopied by knockdown of cellular cholesterol transporters ABCA1 and ABCG1. My goal in this Aim is to prove that the effect of AIBP on embryonic angiogenesis relies on the AIBP function in cholesterol metabolism. These studies will establish a previously unrecognized mechanism connecting cholesterol efflux with embryonic angiogenesis. Then in my independent R00 phase, I will demonstrate that AIBP overexpression in adult zebrafish attenuates heart regeneration. Formation of coronary vasculature is believed to be important for heart regeneration because it conceivably provides resources necessary for robust proliferation of cardiomyocytes. I will make an AIBP conditional expression transgenic fish line, and investigate the impact of AIBP overexpression on angiogenesis that occurs during zebrafish heart regeneration.
My second Aim i n the independent R00 phase is to assess that AIBP expression modulates coronary angiogenesis in mice. Because my results suggest that AIBP limits angiogenesis, I propose that cardiomyocyte-specific loss of AIBP would promote angiogenesis under conditions of cardiac hypertrophy. These studies will elucidate a potential role for AIBP-governed angiogenesis in heart regeneration and in cardiac hypertrophy and suggest possible therapeutic interventions to stimulate the recovery of the microvasculature by promoting angiogenesis.
Myocardial infarction is recognized as a leading cause of mortality and morbidity in the US. Functional microvasculature formation is essential in the recovery of normal cardiac function after reperfusion. Based on my findings that ApoA-I binding protein (AIBP)-mediated cholesterol efflux controls angiogenesis in embryonic zebrafish, I propose to test the hypothesis that AIBP-dependent cholesterol metabolism regulates cardiac angiogenesis under pathologic conditions.
|Fang, Longhou; Liu, Chao; Miller, Yury I (2014) Zebrafish models of dyslipidemia: relevance to atherosclerosis and angiogenesis. Transl Res 163:99-108|
|Fang, Longhou; Choi, Soo-Ho; Baek, Ji Sun et al. (2013) Control of angiogenesis by AIBP-mediated cholesterol efflux. Nature 498:118-22|