ImageJ=1.52d unit=micron 7 January 2021 The gene ZEB2 improves healing after a heart attack in mice Back to news Researchers in the group of Eva van Rooij have found that the gene ZEB2 promotes angiogenesis, the formation of blood vessels, in the heart after a heart attack. They discovered that in mice in which they provided ZEB2 through gene therapy, the hearts were better able to pump blood through the body after a heart attack. This resulted in a better outcome for these mice. The results of their study were published in Nature Communications. During a heart attack, part of the heart no longer receives any oxygen, resulting in a so-called ischemic injury. This results in the loss of muscle cells that are important for pumping blood through the body. These cardiac muscle cells are replaced by a scar, which further impairs the ability of the heart to contract. The group of Eva van Rooij aims to find new factors that may be developed into therapies, to help reduce damage to the heart after a heart attack. ZEB2 (in pink) is expressed at a higher level after an ischemic injury (on the right, white arrows) compared to no injury (on the left). ZEB2 In the current study, the researchers discovered that ZEB2, a transcription factor known to be involved in other processes, was increased in the stressed heart muscle cells, both in mice and humans. A transcription factor is a protein that regulates the expression, or activity, of many genes, and can thereby have a coordinating role in a certain process. “We also found out that the expression of ZEB2 increases immediately after an ischemic injury of the heart, after which it goes back down again. Therefore, we wanted to find out more about the function of ZEB2 in the heart,” says Monika Gladka, first author of this study. Higher amounts of ZEB2 promote angiogenesis. On the left a normal amount of ZEB2, on the right an increased amount of ZEB2. Blood vessels are displayed in pink. Ischemic injury Deleting ZEB2 from cardiac cells in mice during an ischemic injury resulted in worse cardiac function when compared to hearts that had normal levels of ZEB2, which means that the heart needs ZEB2 to heal after ischemic damage. When the researchers genetically increased ZEB2 in heart muscle cells, the hearts of mice after an ischemic injury functioned better – their contractility improved. The researchers found that ZEB2 promoted angiogenesis, the formation of new blood vessels, in the heart. This increased the number of blood vessels that supply the heart with oxygen, explaining why the heart functions better – the heart was exposed to less stress because more oxygen was available. Gene therapy Gladka and her colleagues wanted to know whether ZEB2 could also be used as a therapy. Therefore, the researchers tested a gene therapy method to deliver ZEB2 to the heart of mice immediately after they had a heart attack. This had the same effect as the overexpressing ZEB2 in the genetic model: it increased angiogenesis and resulted in a better outcome for the mice. Gladka: “We discovered a factor that actually controls angiogenesis: the cardiac muscle cells ‘talk’ to the endothelial cells to form new blood vessels.” Future research The researchers applied the ZEB2 gene therapy right at the moment the injury was induced in the mice, which is of course not possible in patients – they only arrive at the hospital for treatment after the heart attack has already taken place. In further experiments, they will test if applying the gene therapy a few hours after an injury also results in better outcomes. Gladka: “Our goal is to find better therapeutic applications and I’m planning to continue working towards this goal in my future research.” ~~~ Publication Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner. Monika M. Gladka, Arwa Kohela, Bas Molenaar, Danielle Versteeg, Lieneke Kooijman, Jantine Monshouwer-Kloots, Veerle Kremer, Harmjan R. Vos, Manon M. H. Huibers, Jody J. Haigh, Danny Huylebroeck, Reinier A. Boon, Mauro Giacca & Eva van Rooij. Nature Communications 2021. Monika Gladka is a postdoc in the group of Eva van Rooij, and will be moving to the Amsterdam Medical Center in February 2021 to start her own line of research as an Assistant Professor in the department of Medical Biology. She will follow up on the research described in the current paper to bring it closer to the clinic. Eva van Rooij is group leader at the Hubrecht Institute and professor of Molecular Cardiology at the UMC Utrecht.
