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Heart bypass without surgery? -- AGGF1 induces therapeutic angiogenesis through autophagy

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This image shows Atg14L siRNA inhibited autophagy induced by AGGF1.

The number of DFCP1-positive puncta was increased by AGGF1 treatment in HUVECs. Knockdown of Atg14L using siRNA significantly decreased the... view more

Credit: Lu et al. (2016)

Coronary artery disease, the number one killer world-wide, restricts and ultimately blocks blood vessels, and cuts off oxygen supply to the heart. A study published on August 11 in the open access journal PLOS Biology reports that treatment with AGGF1, a protein which promotes angiogenesis (the growth of new blood vessels), can successfully treat acute heart attacks in mice. The therapeutic benefits depend on autophagy, a normal breakdown process that removes cellular structures that are damaged or no longer needed and recycles their molecular components.

Therapeutic angiogenesis is an experimental treatment that uses the body's own factors to grow new blood vessels, which in turn can serve as endogenous bypasses of blocked older vessels. Qing Kenneth Wang from Huazhong University of Science and Technology in Wuhan, P. R. China and the Cleveland Clinic in Cleveland, USA, and colleagues study the potential of AGGF1, an angiogenesis-promoting protein present in mice and humans, as a therapeutic agent.

Blood vessels are formed by endothelial cells, and the researchers initially examined the effects of AGGF1 on human endothelial cells. One of the earliest responses to AGGF1 exposure, they found, is the induction of autophagy. Autophagy was detected by molecular markers as well as characteristic changes to the cellular morphology. When the researchers looked at the hearts of mice treated with AGGF1, they found that not just endothelial cells but also other cells types in the heart respond with autophagy.

To examine the connection between AGGF1 induction of both autophagy and angiogenesis, the researchers used drugs that inhibit autophagy. Treatment of endothelial cells exposed to AGGF1 with these drugs, they found, blocks blood vessel formation at the earliest stages, suggesting that autophagy is required for AGGF1-mediated angiogenesis.

When the researchers created mice with mutations in either one or both copies of the Aggf1 gene, they found that mice that don't have any AGGF1 die as embryos. About 60% of mice that have one intact copy, however, survive to adulthood, and those mice have reduced levels of autophagy in their hearts.

The researchers then turned to a mouse model of myocardial infarction (MI). They found that AGGF1 levels increase in the injured heart tissue heart after MI, and that this is likely mediated by hypoxia, i.e., the lack of oxygen, in the affected tissue. Treatment with external AGGF1 following MI increases the number of mice that survive two and four weeks later. It also substantially improves parameters measured by echocardiography as well as other cardiac functions in the treated mice.

Looking at the mechanisms, the researchers report that AGGF1 induces autophagy and angiogenesis, increases the number of cardiac cells that survive, and reduces scarring in the heart compared with mice that had an acute MI but did not receive AGGF1. The researchers also identified a key molecular regulator called JNK that mediates the induction of autophagy by AGGF1; drugs blocking JNK prevent the induction of autophagy by AGGF1. And blocking autophagy by drugs or mutations in genes required for the process abolishes the ability of AGGF1 to promote angiogenesis and cardiac repair after MI, demonstrating again an essential role of autophagy in mediating the beneficial effects of AGFF1.

Acknowledging that it is not yet clear how autophagy activates angiogenesis, the researchers conclude that their data nonetheless "uncover new fundamental molecular mechanisms underlying autophagy and therapeutic angiogenesis and provide a novel treatment strategy for [coronary artery disease] and MI, the leading cause of sudden death worldwide".

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In your coverage please use this URL to provide access to the freely available article in PLOS Biology: http://dx.plos.org/10.1371/journal.pbio.1002529

Citation: Lu Q, Yao Y, Hu Z, Hu C, Song Q, Ye J, et al. (2016) Angiogenic Factor AGGF1 Activates Autophagy with an Essential Role in Therapeutic Angiogenesis for Heart Disease. PLoS Biol 14(8): e1002529. doi:10.1371/journal.pbio.1002529

Funding: This study was funded by the National Natural Science Foundation of China grants 91439129 and 31430047, the National Basic Research Program of China (973 Programs: 2013CB531101 and 2012CB517801), the Natural Science Key Program of Hubei Province (2014CFA074), the Hubei Province's Outstanding Medical Academic Leader program, the "Innovative Development of New Drugs" Key Scientific Project (2011ZX09307-001-09), the Specialized Research Fund for the Doctoral Program of Higher Education from the Ministry of Education (20120142110076), the National Natural Science Foundation of China grants NSFC-J1103514 and by the National Institutes of Health grants R01 HL121358 and R01 HL126729. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

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