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MHH researchers have discovered a previously unknown signalling pathway involved in the formation of new blood vessels to aid recovery in the affected area.
Every year, more than 200,000 people in Germany suffer a heart attack. This is caused by blocked coronary arteries. As a result, part of the heart muscle is no longer supplied with sufficient blood and oxygen; the tissue dies within a few hours and forms scar tissue. Severe heart failure (cardiac insufficiency) is a possible consequence. Unlike the liver, the heart of an adult human is barely capable of regenerating. However, it is able to initiate repair processes. Monocytes – white blood cells from the bone marrow and spleen – are involved in this. In the heart, these immune cells mature into macrophages (scavenger cells), remove the dead heart muscle cells and promote healing of the infarct. Until now, it was not precisely known which signalling pathways were responsible for this. Now, a research team led by Prof. Dr Kai Wollert, Head of Molecular and Translational Cardiology at the Department of Cardiology and Angiology at Hannover Medical School (MHH), has discovered that a microprotein called BRICK1 plays a key role in this process. This small protein not only stimulates the endothelial cells inside the blood vessels to form new vessels and repair the infarct tissue; it also protects the heart muscle cells that are still functioning in the infarct region. The findings have been published in the prestigious journal ‘Science Translational Medicine’.
First discovered in the leaves of maize plants
BRICK1 consists of just 75 individual building blocks, known as amino acids, and is widespread throughout the plant and animal kingdoms. “The protein was originally discovered in maize,” says Professor Wollert. “If the associated gene is mutated, the cells of the leaf epidermis take on a brick-like shape, whereas they normally have lobed edges – hence the name ‘brick’.” The gene has hardly changed over the course of evolution. The BRICK1 microproteins from mice and humans differ by just a single amino acid. Until now, it was only known that BRICK1, as a component of the cytoskeleton, controls processes such as cell movement, cell division and cell shaping. Following a heart attack, the researchers were able to detect it in the blood – that is, outside cells – in both mice and patients. But how did the microprotein get there?
Release following a heart attack
The research team was able to demonstrate that BRICK1 is released by macrophages. This occurs when these cells die after their 24-hour clean-up work in the area affected by the heart attack and their cell membrane becomes permeable. The spent immune cells are then replaced by new macrophages. “We investigated in a mouse model of heart attack what effects occur when the BRICK1 gene is absent in macrophages or when we specifically intercept the microprotein outside the cells using an antibody,” explains Dr Felix Polten, research fellow in the cardiology research group and first author of the study. The result: without BRICK1, microvascular formation in the infarct area was disrupted, leading to severe heart failure. Conversely, treatment with the microprotein improved cardiac function in mice following a heart attack by protecting heart muscle cells and promoting increased vascular formation.
Both the measurement of BRICK1 concentrations in the blood and the elucidation of the reparative signalling pathways in endothelial cells were carried out at the Core Facility Proteomics at MHH. “Using two specialised mass spectrometers, we were able to elucidate how BRICK1 stimulates cell division,” says Prof. Dr Andreas Pich, head of this central research facility.
Patent application and clinical trials
“The release mechanism from dying inflammatory cells that we have identified is novel and unexpected,” emphasises Professor Wollert. Until now, it was only known that heart muscle cells damaged following a heart attack release various proteins and small molecules, some of which trigger the inflammatory response that clears away the dead heart muscle tissue and replaces it with connective tissue. In contrast, the release of BRICK1 only occurs during the repair process, i.e. significantly later. Because BRICK1 has therapeutic potential, the researchers have filed a patent application for the use of the microprotein. They are now seeking an industry partner for clinical trials. These are intended to show whether treatment with the microprotein could help patients minimise the damage caused by a heart attack following a blockage and improve wound healing in the days following the attack.
SERVICE:
Further information is available from Prof. Dr Kai Wollert, wollert.kai@mh-hannover.de.
The original paper “Extracellular BRICK1 drives heart repair after myocardial infarction in mice” can be found here: https://www.science.org/doi/10.1126/scitranslmed.adx2876
Have clarified the role of the microprotein BRICK1 in heart attacks (from left): Prof. Dr Andreas Pi ...
Copyright: Karin Kaiser/MHH
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Have clarified the role of the microprotein BRICK1 in heart attacks (from left): Prof. Dr Andreas Pi ...
Copyright: Karin Kaiser/MHH
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