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Cambridge Cardiovascular

 

Spotlight on Research

This page collects research news and articles that we have published into one place. The purpose of this page is to highlight some ongoing projects that will benefit patients in future and to give more visibility to BHF-funded Group Leaders and Research Associates. Please contact Denise Hatherly if you would like your research to be featured here.

 

Marginal zone B cells produce ‘natural’ atheroprotective IgM antibodies in a T cell–dependent manner

Meritxell Nus and colleagues* studied how the adaptive immune response plays an important role in atherosclerosis. In response to a high-fat/high-cholesterol (HF/HC) diet, marginal zone B (MZB) cells activate an atheroprotective programme by regulating the differentiation and accumulation of ‘poorly differentiated’ T follicular helper (Tfh) cells. On the other hand, Tfh cells activate the germinal centre response, which promotes atherosclerosis through the production of class-switched high-affinity antibodies. They therefore investigated the direct role of Tfh cells and the role of IL18 in Tfh differentiation in atherosclerosis.

Their findings revealed a previously unsuspected role of MZB cells in regulating atheroprotective ‘natural’ IgM antibody production in a Tfh-dependent manner, which could have important pathophysiological and therapeutic implications.

 

*James Harrison, Stephen A Newland, Wei Jiang, Despoina Giakomidi, Xiaohui Zhao, Marc Clement, Leanne Masters,  Andrej Corovic, Xian Zhang, Fabrizio Drago, Marcella Ma, Maria Ozsvar Kozma, Froher Yasin, Yuta Saady, Hema Kothari, Tian X Zhao, Guo-Ping Shi, Coleen A McNamara, Christoph J Binder,  Andrew P SageJason M TarkinZiad Mallat

Link to paper

 

A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases

Alessandra Granata (Clinical Neurosciences) and colleagues have grown small blood vessel-like models in the lab and used them to show how damage to the scaffolding that supports these vessels can cause them to leak, leading to conditions such as vascular dementia and stroke. Cerebral small vessel disease (SVD) affects the small vessels in the brain and is a leading cause of stroke and dementia. Emerging evidence supports a role of the extracellular matrix (ECM), at the interface between blood and brain, in the progression of SVD pathology, but this remains poorly characterized. To address ECM role in SVD, we developed a co-culture model of mural and endothelial cells using human induced pluripotent stem cells from patients with COL4A1/A2 SVD-related mutations. This model revealed that these mutations induce apoptosis, migration defects, ECM remodeling, and transcriptome changes in mural cells. Importantly, these mural cell defects exert a detrimental effect on endothelial cell tight junctions through paracrine actions. COL4A1/A2 models also express high levels of matrix metalloproteinases (MMPs), and inhibiting MMP activity partially rescues the ECM abnormalities and mural cell phenotypic changes. These data provide a basis for targeting MMP as a therapeutic opportunity in SVD. Coverage included: TimesIndependentEvening Standard and ABC (Spanish) newspapers.

Link to paper

 

A rare selenoprotein deficiency disorder predisposes to aortic aneurysm formation.

Aortic aneurysms, which may dissect or rupture acutely and be fatal, can have a heritable basis. In a rare example, local patients with a deficiency of selenocysteine-containing proteins, due to defects in a gene (SECISBP2) which controls their production, were found to develop progressive, aneurysmal dilatation of the ascending aorta at a young age. In research published in Nature Communications, Erik Schoenmakers (Chatterjee group, Wellcome-MRC Institute of Metabolic Science), Helle Jørgensen and Martin Bennett (Cardiorespiratory Medicine), working with clinical (CUH, RPH) and basic (Mike Murphy, MRC MBU) colleagues, have established a causal relationship, showing that aortas from patients or mice (with vascular smooth muscle cell-specific) selenoprotein deficiency exhibit oxidative stress-mediated cell death, including via ferroptosis, leading to aortic degeneration. Mitochondria-targeted antioxidant exposure prevents oxidative damage in patient’s cells and aortopathy in a zebrafish model, raising the possibility of such therapies in this new syndromic cause of aortic aneurysm. Published 02 December 2023.

Link to paper

 

PLK1 inhibition dampens NLRP3 inflammasome–elicited response in inflammatory disease models

A cancer drug currently in the final stages of clinical trials could offer hope for the treatment of a wide range of inflammatory diseases, including gout, heart failure, cardiomyopathy, and atrial fibrillation. "We believe [our findings] could be important in preventing a number of common diseases that can cause pain and disability and in some cases can lead to life-threatening complications" - Xuan Li 

In a study published on 1 November 2023 in the Journal of Clinical Investigation, the researchers have identified a molecule that plays a key role in triggering inflammation in response to materials in the body seen as potentially harmful.

We are born with a defence system known as innate immunity, which acts as the first line of defence against harmful materials in the body. Some of these materials will come from outside, such as bacterial or viral infections, while others can be produced within the body.

Innate immunity triggers an inflammatory response, which aims to attack and destroy the perceived threat. But sometimes, this response can become overactive and can itself cause harm to the body.

One such example of this is gout, which occurs when urate crystals build up in joints, causing excessive inflammation, leading to intense pain. Another example is heart attack, where dead cell build up in the damaged heart – the body sees itself as being under attack and an overly-aggressive immune system fights back, causing collateral damage to the heart.

Several of these conditions are characterised by overactivation of a component of the innate immune response known as an inflammasome – specifically, the inflammasome NLRP3. Scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute at Cambridge have found a molecule that helps NLRP3 respond.

This molecule is known as PLK1. It is involved in a number of processes within the body, including helping organise tiny components of our cells known as microtubules cytoskeletons. These behave like train tracks inside of the cell, allowing important materials to be transported from one part of the cell to another.

 

Link to paper

Link to article in the Sunday Mirror

 

Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance (April 2022)

Pellegrinelli V et al Nat Metabolism.

Our paper identifies Peptidase D (PEPD) as an essential protein for the development of adipose tissue dysfunction, fibro-inflammation, and insulin resistance in obesity. PEPD gene can explain the metabolically healthy obese and unhealthy non-obese paradox by providing a mechanism that uncouples fat mass expansion from its fibro-inflammatory complications. This is possible because PEPD has two functions: a) PEPD is an enzyme that controls collagen turnover and, consequently, fibrosis deposition, and also b) it is a secreted protein that signals through the EGF receptors exacerbating fibrosis and inflammation.


Our paper, led by Dr Pellegrinelli, shows that in human and murine obesity, the expression of PEPD and its enzymatic activity is decreased in adipose tissue macrophages facilitating the development of fibrosis and adipose tissue dysfunctions. On the other hand, in obesity, PEPD is secreted from macrophages and promotes inflammation and insulin resistance. We have used insights from human genetics, human cohorts, fibro-inflammatory cell and murine models, molecular profiling, and computing biology to show that PEPD produced by the macrophages in adipose tissue might serve as a biomarker of fibro-inflammation and insulin resistance and could represent a therapeutic target to prevent or reverse fibrosis and obesity-associated insulin resistance and type 2 diabetes.

This is a major effort from many laboratories through a broad international collaboration, including laboratories from Paris, Bielefeld, Nanjing, Girona, Valencia, Taiwan, Bari, Uppsala, London, New York, and Copenhagen. We are very thankful for the funding bodies that have supported this global collaboration, particularly MRC and British Heart Foundation supporting us here in Cambridge and the agencies supporting our collaborators.

Link to paper

 

Pericoronary adipose tissue density is associated with inflammatory disease activity in Takayasu arteritis (September 2021)

Inflammation of the main arteries that supply blood to the heart is associated with changes in the density of surrounding fat, which can be detected using a CT scan. Research at the University of Cambridge led by Dr Christopher Wall and Dr Jason Tarkin found this method to be accurate for identifying active arterial inflammation in patients with a rare form of systemic vasculitis, called Takayasu arteritis. Coronary artery involvement is common in Takayasu arteritis, and there is a clinical need for a better method of identifying inflammation in these vessels than is currently available. For this work, Dr Wall received the Young Investigator Award at the British Society of Cardiovascular Imaging 2021 conference held in Oxford. This research published in the European Heart Journal Open was performed in collaboration with Dr James Rudd, Professor Justin Mason (Imperial College London) and Dr Damini Dey (Cedars-Sinai Medical Centre, Los Angeles), among others. It was funded by the Wellcome Trust and supported by the Cambridge BHF Centre of Research Excellence.


 

(Representative images showing increased fat density surrounding the right coronary artery of a patient with Takayasu arteritis and bilateral coronary artery aneurysms)

Link to paper

 

Radiomics in stroke medicine: assessing robustness and feasibility for stroke prevention

A cross-discipline group of researchers, led by MB PhD student Elizabeth Le and PI James Rudd, have published in Nature Scientific Reports the first attempt to determine whether radiomics might be useful for predicting stroke in patients with carotid artery disease. Radiomics refers to the harnessing of information 'hidden' within medical images for diagnostic and prognostic purposes, and is being increasingly used in oncology

Nature 2021 feb

Read more here

 

CRE Funded projects

A new online series of short personal interviews with Cambridge Stem Cell Institute researchers exploring how they are adapting their research to investigate Covid-19.

In this film Dr Cédric Ghevaert introduces his group, who are investigating blood clotting in coronavirus patients. Amie, James, Moyra and Winnie answered our questions about the team’s recent work with collaborators at the University of Bristol.
 

Responsive Research

Dr Maria Colzani reveals in this interview how the Sinha lab are using stem cell & cardiovascular expertise to investigate heart damage in covid patients with funding from BHF Centre of Regenerative Medicine.

 

Professor Toni Vidal-Puig, Reflecting on the Covid-19 pandemic and its impact on the research landscape

Professor Antonio Vidal-Puig is Professor of Molecular Nutrition and Metabolism at the University of Cambridge. Reflecting on the Covid-19 pandemic and its impact on the research landscape. Toni tells in this interview with the BHF how the BHF CRE have supported the research, about fundraising for PPE, testing the strength of global networks, and what we can learn from the crisis ​

 

BHF CRE Funded Covid projects

Cambridge Investigation of Cardiac Complications of Severe COVID-19 (CICERO-19) - Dr Sanjay Sinha, Prof. Anthony Davenport (Clinical Pharmacology), Prof. Paul Lehner (Medicine), Dr Nick Matheson (Medicine).

Molecular mechanism underlying late-stage pathology in COVID19 – platelets and megakaryocytes- Cedric Ghevaert, Amie Waller

For any information or queries related to Covid-19 topics regarding Cambridge Infectious Diseases IRC, Cambridge Immunology Network SRN, and the Cambridge Cardiovascular IRC, please email covid-response@cam.ac.uk and include CINCID in the subject line.

The Naked Scientists: Covid-19

150 scientists from new institute join Cambridge fight against COVID-19

 

Past Articles

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