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Angiogenic Factor AGGF1 Activates Autophagy with an Essential Role in Therapeutic Angiogenesis for Heart Disease

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Angiogenic Factor AGGF1 Activates Autophagy with an Essential Role in Therapeutic Angiogenesis for Heart Disease RESEARCH ARTICLE Angiogenic Factor AGGF1 Activates Autophagy with an Essential Role in Therapeutic Angiogenesis for Heart Disease Qiulun Lu1☯, Yufeng Yao1☯, Zhenkun Hu1, Changqing Hu1, Qixue Song1, Jian Ye1, Chengqi Xu1, Annabel Z. Wang2, Qiuyun Chen3,4, Qing Kenneth Wang1,3,4,5* 1 Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, P. R. China, 2 Duke University, Durham, North Carolina, United States of America, 3 Center for a11111 Cardiovascular Genetics, Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, United States of America, 4 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America, 5 Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America ☯ These authors contributed equally to this work. * [email protected]; [email protected] OPEN ACCESS Citation: Lu Q, Yao Y, Hu Z, Hu C, Song Q, Ye J, et Abstract al. (2016) Angiogenic Factor AGGF1 Activates Autophagy with an Essential Role in Therapeutic AGGF1 is an angiogenic factor with therapeutic potential to treat coronary artery disease Angiogenesis for Heart Disease. PLoS Biol 14(8): (CAD) and myocardial infarction (MI). However, the underlying mechanism for AGGF1- e1002529. doi:10.1371/journal.pbio.1002529 mediated therapeutic angiogenesis is unknown. Here, we show for the first time that Academic Editor: Cecilia W. Lo, University of AGGF1 activates autophagy, a housekeeping catabolic cellular process, in endothelial cells Pittsburgh, UNITED STATES (ECs), HL1, H9C2, and vascular smooth muscle cells. Studies with Atg5 small interfering Received: February 12, 2016 RNA (siRNA) and the autophagy inhibitors bafilomycin A1 (Baf) and chloroquine demon- Accepted: July 12, 2016 strate that autophagy is required for AGGF1-mediated EC proliferation, migration, capillary Published: August 11, 2016 tube formation, and aortic ring-based angiogenesis. Aggf1+/- knockout (KO) mice show Copyright: © 2016 Lu et al. This is an open access reduced autophagy, which was associated with inhibition of angiogenesis, larger infarct article distributed under the terms of the Creative areas, and contractile dysfunction after MI. Protein therapy with AGGF1 leads to robust Commons Attribution License, which permits recovery of myocardial function and contraction with increased survival, increased ejection unrestricted use, distribution, and reproduction in any fraction, reduction of infarct areas, and inhibition of cardiac apoptosis and fibrosis by pro- medium, provided the original author and source are credited. moting therapeutic angiogenesis in mice with MI. Inhibition of autophagy in mice by bafilo- mycin A1 or in Becn1+/- and Atg5 KO mice eliminates AGGF1-mediated angiogenesis and Data Availability Statement: All relevant data are within the paper and its Supporting Information files. therapeutic actions, indicating that autophagy acts upstream of and is essential for angio- genesis. Mechanistically, AGGF1 initiates autophagy by activating JNK, which leads to acti- Funding: This study was funded by the National Natural Science Foundation of China grants vation of Vps34 lipid kinase and the assembly of Becn1-Vps34-Atg14 complex involved in 91439129 and 31430047 (http://www.nsfc.gov.cn/), the initiation of autophagy. Our data demonstrate that (1) autophagy is essential for effective the National Basic Research Program of China (973 therapeutic angiogenesis to treat CAD and MI; (2) AGGF1 is critical to induction of autop- Programs: 2013CB531101 and 2012CB517801) (http://program.most.gov.cn/), the Natural Science Key hagy; and (3) AGGF1 is a novel agent for treatment of CAD and MI. Our data suggest that Program of Hubei Province (2014CFA074) (http:// maintaining or increasing autophagy is a highly innovative strategy to robustly boost the effi- www.hbstd.gov.cn/), the Hubei Province’s Outstanding cacy of therapeutic angiogenesis. Medical Academic Leader program, the “Innovative Development of New Drugs” Key Scientific Project (2011ZX09307-001-09) (http://www.nmp.gov.cn/), the PLOS Biology | DOI:10.1371/journal.pbio.1002529 August 11, 2016 1/30 Targeting AGGF1 for Therapy of Coronary Heart Disease Specialized Research Fund for the Doctoral Program of Higher Education from the Ministry of Education Author Summary (20120142110076) (http://www.cutech.edu.cn/), the National Natural Science Foundation of China grants Coronary artery disease is the number one killer disease worldwide. Recently, therapeutic NSFC-J1103514 (http://www.nsfc.gov.cn/) and by the angiogenesis has been proposed as an attractive new strategy for treating this and other National Institutes of Health grants R01 HL121358 ischemic diseases. This study establishes the angiogenic factor AGGF1 as a novel target and R01 HL126729 (http://www.nih.gov/). The funders and agent that can successfully treat coronary artery disease and acute myocardial infarc- had no role in study design, data collection and tion and dramatically improve survival and cardiac function in mouse models. We present analysis, decision to publish, or preparation of the manuscript. the unexpected finding that AGGF1 has these effects via activating autophagy, and that autophagy is essential for therapeutic angiogenesis in animals. We find that AGGF1 is a Competing Interests: The authors have declared novel master regulator of autophagy not only in endothelial cells but also in all other cell that no competing interests exist. types examined in the study. Mechanistically, AGGF1 activates autophagy by activating Abbreviations: AGGF1, Angiogenic Factor With G- JNK, which leads to activation of the Vps34 lipid kinase and assembly of the Becn1- Patch And FHA Domains; AMBRA1, Autophagy And Vps34-Atg14 complex involved in the initiation of autophagy. The study thus provides a Beclin 1 Regulator 1; Baf, Bafilomycin A1; CABG, Coronary Artery Bypass Surgery; CAD, Coronary link connecting the therapeutic angiogenesis and autophagy pathways in heart disease. Artery Disease; CQ, Chloroquine; dNTP, deoxyribose nucleoside triphosphate; ECs, Endothelial Cells; ER, Endoplasmic Reticulum; FGF2, Fibroblast Growth Factor 2; GFP, Green Fluorescent Protein; HPF, High-Power Field; HUVECs, Human Umbilical Vein Introduction Endothelial Cells; HW, Heart Weight; IgG, AGGF1 is an Angiogenic factor with a G-patch domain and a Forkhead-associated (FHA) Immunoglobin G; JNK, c-Jun N-terminal protein kinase; KO, knockout; KTS, Klippel–Trénaunay domain. AGGF1 was initially identified by our laboratory through positional cloning analysis for syndrome; LAD, Left Anterior Descending; LC3, Light a gene involved in development of Klippel–Trénaunay syndrome (KTS), a congenital vascular Chain 3; LV, Left Ventricular; LVEDD, Left Ventricular disorder [1]. AGGF1 can induce angiogenesis and excessive angiogenesis, and increased AGGF1 End-Diastolic Diameter; LVEF, Left Ventricular expression is a cause of KTS [1–5]. We and others have also found that AGGF1 is critical to spec- Ejection Fraction; LVESD, Left Ventricular End- ification of veins [6,7], specification of multipotent hemangioblasts [8], and anti-inflammation Systolic Diameter; LVFS, Left Ventricular Fraction Shortening; MI, Myocardial Infarction; PARP, Poly [9]. However, the molecular mechanisms underlying these processes remain to be fully defined. (ADP-ribose) polymerase; PCI, Percutaneous Coronary artery disease (CAD) and its most severe manifestation, myocardial infarction (MI), Coronary Intervention; RT, Reverse transcription; are the most common causes of death worldwide. Therapeutic angiogenesis has been proposed as siRNA, small interfering RNA; SNARE, Soluble N- an attractive new strategy to treat CAD and MI patients. Therapeutic angiogenesis can be defined ethylmaleimide-sensitive factor attachment protein as the utilization of angiogenic growth factors to promote neovascularization and growth of col- receptor; TL, Tibia Length; ULK1, Unc-51 Like lateral blood vessels, which act as endogenous bypass conduits to improve blood flow and Autophagy Activating Kinase 1; VEGF, vascular endothelial growth factors increase tissue perfusion in the ischemic extremity. However, there is currently no United States Food and Drug Administration (FDA)-approved therapeutic angiogenesis to treat CAD, MI, or other ischemic diseases [10,11]. Many challenges must be overcome before therapeutic angiogen- esis becomes an applied patient therapy, including the critical identification of the most robust, effective angiogenic factor [10,11]. Importantly, lack of understanding of the fundamental molec- ular mechanisms underlying therapeutic angiogenesis has slowed advances in this field. Autophagy is an evolutionarily conserved dynamic catabolic process that removes damaged, dysfunctional organelles and long-lived protein aggregates [12]. It recycles amino acids and other substrates for protein synthesis and ATP generation [12]. However, excessive autophagy can also lead to cell death. Autophagy is initiated by the formation of the phagophore; this pro- cess is mediated by the class III PI3-K complex consisting of Vps34, Vps15, Atg14, and beclin 1 [12]. The phagophore then elongates and engulfs cytoplasmic materials targeted for degrada- tion, leading to the formation of autophagosome. During this process, the microtubule-associ- ated protein 1 light
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