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

Autor: Qing Kenneth Wang, Qixue Song, Jian Ye, Qiuyun Chen, Yufeng Yao, Changqing Hu, Chengqi Xu, Annabel Z. Wang, Zhenkun Hu, Qiulun Lu
Rok vydání: 2016
Předmět:
0301 basic medicine
Small interfering RNA
Physiology
Angiogenesis
Myocardial Infarction
Apoptosis
030204 cardiovascular system & hematology
Cardiovascular Physiology
Biochemistry
Muscle
Smooth
Vascular
Diagnostic Radiology
Autophagy-Related Protein 5
Neovascularization
0302 clinical medicine
Ultrasound Imaging
Medicine and Health Sciences
Small interfering RNAs
Myocytes
Cardiac
Biology (General)
Angiogenic Proteins
Enzyme Inhibitors
Cells
Cultured
Mice
Knockout
Cell Death
Neovascularization
Pathologic
Kinase
Radiology and Imaging
General Neuroscience
Heart
Animal Models
BECN1
Recombinant Proteins
3. Good health
Nucleic acids
Cell Processes
Echocardiography
Beclin-1
Macrolides
Anatomy
medicine.symptom
General Agricultural and Biological Sciences
Research Article
Heart Diseases
QH301-705.5
Imaging Techniques
Autophagic Cell Death
Blotting
Western
Myocytes
Smooth Muscle
ATG5
Cardiology
Neovascularization
Physiologic
Mouse Models
Biology
Research and Analysis Methods
General Biochemistry
Genetics and Molecular Biology
Cell Line
03 medical and health sciences
Model Organisms
Diagnostic Medicine
Genetics
Autophagy
Human Umbilical Vein Endothelial Cells
medicine
Animals
Humans
Therapeutic angiogenesis
Non-coding RNA
General Immunology and Microbiology
Biology and Life Sciences
Cell Biology
Gene regulation
Mice
Inbred C57BL
030104 developmental biology
Immunology
Cardiovascular Anatomy
Cancer research
RNA
Gene expression
Developmental Biology
Zdroj: PLoS Biology
PLoS Biology, Vol 14, Iss 8, p e1002529 (2016)
ISSN: 1545-7885
DOI: 10.1371/journal.pbio.1002529
Popis: AGGF1 is an angiogenic factor with therapeutic potential to treat coronary artery disease (CAD) and myocardial infarction (MI). However, the underlying mechanism for AGGF1-mediated therapeutic angiogenesis is unknown. Here, we show for the first time that AGGF1 activates autophagy, a housekeeping catabolic cellular process, in endothelial cells (ECs), HL1, H9C2, and vascular smooth muscle cells. Studies with Atg5 small interfering RNA (siRNA) and the autophagy inhibitors bafilomycin A1 (Baf) and chloroquine demonstrate that autophagy is required for AGGF1-mediated EC proliferation, migration, capillary tube formation, and aortic ring-based angiogenesis. Aggf1+/- knockout (KO) mice show reduced autophagy, which was associated with inhibition of angiogenesis, larger infarct areas, and contractile dysfunction after MI. Protein therapy with AGGF1 leads to robust recovery of myocardial function and contraction with increased survival, increased ejection fraction, reduction of infarct areas, and inhibition of cardiac apoptosis and fibrosis by promoting therapeutic angiogenesis in mice with MI. Inhibition of autophagy in mice by bafilomycin A1 or in Becn1+/- and Atg5 KO mice eliminates AGGF1-mediated angiogenesis and therapeutic actions, indicating that autophagy acts upstream of and is essential for angiogenesis. Mechanistically, AGGF1 initiates autophagy by activating JNK, which leads to activation of Vps34 lipid kinase and the assembly of Becn1-Vps34-Atg14 complex involved in the initiation of autophagy. Our data demonstrate that (1) autophagy is essential for effective therapeutic angiogenesis to treat CAD and MI; (2) AGGF1 is critical to induction of autophagy; and (3) AGGF1 is a novel agent for treatment of CAD and MI. Our data suggest that maintaining or increasing autophagy is a highly innovative strategy to robustly boost the efficacy of therapeutic angiogenesis.
Treatment with the angiogenic factor AGGF1 dramatically improves survival and cardiac function in mouse models for coronary artery disease and myocardial infarction by activating autophagy and angiogenesis.
Author Summary Coronary artery disease is the number one killer disease worldwide. Recently, therapeutic angiogenesis has been proposed as an attractive new strategy for treating this and other ischemic diseases. This study establishes the angiogenic factor AGGF1 as a novel target and agent that can successfully treat coronary artery disease and acute myocardial infarction and dramatically improve survival and cardiac function in mouse models. We present 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 novel master regulator of autophagy not only in endothelial cells but also in all other cell types examined in the study. Mechanistically, AGGF1 activates autophagy by activating JNK, which leads to activation of the Vps34 lipid kinase and assembly of the Becn1-Vps34-Atg14 complex involved in the initiation of autophagy. The study thus provides a link connecting the therapeutic angiogenesis and autophagy pathways in heart disease.
Databáze: OpenAIRE
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