̽��ֱ�� of Cambridge - Department of Cardiovascular Medicine

Could a vaccine protect us against heart attacks?

cjb250 — Thu, 20 May 2021 07:15:46 +0000

Professor Ziad Mallat and his team have been shortlisted for a £30 million grant from the British Heart Foundation. If successful, atherosclerosis – hardening of the arteries – could become a thing of the past.

Observation of blood vessel cells changing function could lead to early detection of blocked arteries

cjb250 — Thu, 01 Nov 2018 10:00:25 +0000

̽��ֱ��muscle cells that line the blood vessels have long been known to multi-task. While their main function is pumping blood through the body, they are also involved in ‘patching up’ injuries in the blood vessels. Overzealous switching of these cells from the ‘pumping’ to the ‘repair’ mode can lead to atherosclerosis, resulting in the formation of ‘plaques’ in the blood vessels that block the blood flow.

Using state-of-the art genomics technologies, an interdisciplinary team of researchers based in Cambridge and London has caught a tiny number of vascular muscle cells in mouse blood vessels in the act of switching and described their molecular properties. ̽��ֱ��researchers used an innovative methodology known as single-cell RNA-sequencing, which allows them to track the activity of most genes in the genome in hundreds of individual vascular muscle cells.

Their findings, published today in Nature Communications, could pave the way for detecting the ‘switching’ cells in humans, potentially enabling the diagnosis and treatment of atherosclerosis at a very early stage in the future.

Atherosclerosis can lead to potentially serious cardiovascular diseases such as heart attack and stroke. Although there are currently no treatments that reverse atherosclerosis, lifestyle interventions such as improved diet and increased exercise can reduce the risk of the condition worsening; early detection can minimise this risk.

“We knew that although these cells in healthy tissues look similar to each other, they are actually quite a mixed bag at the molecular level,” explains Dr Helle Jørgensen, a group leader at the ̽��ֱ�� of Cambridge’s Division of Cardiovascular Medicine, who co-directed the study. “However, when we got the results, a very small number of cells in the vessel really stood out. These cells lost the activity of typical muscle cell genes to various degrees, and instead expressed a gene called Sca1 that is best known to mark stem cells, the body’s ‘master cells’.”

̽��ֱ��ability to detect the activity (or ‘expression’) of thousands of genes in parallel in these newly-discovered cells has been a game-changer, say the researchers.

“Single-cell RNA-sequencing has allowed us to see that in addition to Sca1, these cells expressed a whole set of other genes with known roles in the switching process,” says Lina Dobnikar, a computational biologist based at Babraham Institute and joint first author on the study. “While these cells did not necessarily show the properties of fully-switched cells, we could see that we caught them in the act of switching, which was not possible previously.”

To confirm that these unusual cells originated from muscle cells, the team used another new technology, known as lineage labelling, which allowed the researchers to trace the history of a gene’s expression in each cell.

“Even when the cells have entirely shut down muscle cell genes, lineage labelling demonstrated that at some point either they or their ancestors were indeed the typical muscle cells,” says Annabel Taylor, a cell biologist in Jørgensen’s lab and joint first author on the study.

Knowing the molecular profile of these unusual cells has made it possible to study their behaviour in disease. Researchers have confirmed that these cells become much more numerous in damaged blood vessels and in atherosclerotic plaques, as would be expected from switching cells.

“We were fortunate in that single-cell RNA-sequencing technologies had been rapidly evolving while we were working on the project,” says Dr Mikhail Spivakov, a genomics biologist and group leader at MRC London Institute of Medical Sciences, who co-directed the study with Jørgensen. Dr Spivakov carried out the work while he was a group leader at the Babraham Institute. “When we started out, looking at hundreds of cells was the limit, but for the analysis of atherosclerotic plaques we really needed thousands. By the time we got to doing this experiment, it was already possible.”

In the future, the findings by the team may pave the way for catching atherosclerosis early and treating it more effectively.

“Theoretically, seeing an increase in the numbers of switching cells in otherwise healthy vessels should raise an alarm”, says Jørgensen. “Likewise, knowing the molecular features of these cells may help selectively target them with specific drugs. However, it is still early days. Our study was done in mice, where we could obtain large numbers of vascular muscle cells and modify their genomes for lineage labelling. Additional research is still required to translate our results into human cells first and then into the clinic.”

̽��ֱ��research was funded by the British Heart Foundation and UK Research and Innovation.

Reference
Dobnikar, L, Taylor, AL et al. Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy vessels. Nature Communications; 1 Nov 2019; DOI: 10.1038/s41467-018-06891-x

A study in mice has shown that it may be possible to detect the early signs of atherosclerosis, which leads to blocked arteries, by looking at how cells in our blood vessels change their function.

Annie Cavanagh

Blood clot forming in arterial plaque

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New research allows doctors to image dangerous ‘hardening’ of the arteries

cjb250 — Fri, 10 Jul 2015 08:21:49 +0000

̽��ֱ��technique, reported in the journal Nature Communications, could help in the diagnosis of these conditions in at-risk patients and in the development of new medicines.

Atherosclerosis – hardening of the arteries – is a potentially serious condition where arteries become clogged by a build-up of fatty deposits known as ‘plaques’. One of the key constituents in these deposits is calcium. In some people, pieces from the calcified artery can break away – if the artery supplies the brain or heart with blood, this can lead to stroke or heart attack.

“Hardening, or ‘furring’, of the arteries can lead to very serious disease, but it’s not clear why the plaques are stable in some people but unstable in others,” explains Professor David Newby, the BHF John Wheatley Professor of Cardiology at the Centre for Cardiovascular Science, ̽��ֱ�� of Edinburgh. “We need to find new methods of identifying those patients at greatest risk from unstable plaques.”

̽��ֱ��researchers injected patients with sodium fluoride that had been tagged with a tiny amount of a radioactive tracer. Using a combination of scanning techniques (positron emission tomography (PET) and computed tomography (CT)), the researchers were able to track the progress of the tracer as it moved around the body.

“Sodium fluoride is commonly found in toothpaste as it binds to calcium compounds in our teeth’s enamel,” says Dr Anthony Davenport from the Department of Experimental Medicine and Immunotherapeutics at the ̽��ֱ�� of Cambridge, who led the study. “In a similar way, it also binds to unstable areas of calcification in arteries and so we’re able to see, by measuring the levels of radioactivity, exactly where the deposits are building up. In fact, this new emerging technique is the only imaging platform that can non-invasively detect the early stages of calcification in unstable atherosclerosis.”

Following their sodium fluoride scans, the patients had surgery to remove calcified plaques and the extracted tissue was imaged, this time at higher resolution, using a laboratory PET/CT scanner and an electron microscope. This confirmed that the radiotracer accumulates in areas of active, unstable calcification whilst avoiding surrounding tissue.

Dr James Rudd, a cardiologist and researcher from the Department of Cardiovascular Medicine at the ̽��ֱ�� of Cambridge adds: “Sodium fluoride is a simple and inexpensive radiotracer that should revolutionise our ability to detect dangerous calcium in the arteries of the heart and brain. This will allow us to use current treatments more effectively, by giving them to those patients at highest risk. In addition, after further work, it may be possible to use this technique to test how well new medicines perform at preventing the development of atherosclerosis.”

̽��ֱ��Wellcome Trust provided the majority of support for this study, with additional contributions from the British Heart Foundation, Cancer Research UK and the Cambridge NIHR Biomedical Research Centre.

Reference
Irkle, A et al. Identifying active vascular microcalcification by 18F-sodium fluoride positron emission tomography. Nature Communications; 7 July 2015.

Researchers at the ̽��ֱ�� of Cambridge, in collaboration with the ̽��ֱ�� of Edinburgh, have shown how a radioactive agent developed in the 1960s to detect bone cancer can be re-purposed to highlight the build-up of unstable calcium deposits in arteries, a process that can cause heart attack and stroke.

Sodium fluoride is a simple and inexpensive radiotracer that should revolutionise our ability to detect dangerous calcium in the arteries of the heart and brain

James Rudd

̽��ֱ�� of Cambridge

Imaging atherosclerotic calcification or ‘hardening of the arteries’ using positron emission tomography

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