Inhibitory signal pathways identified

May 8, 2017, Ludwig Maximilian University of Munich
Inhibitory signal pathways identified
An atherosclerotic lesion in the mouse. Credit: Döring Research Group

LMU researchers led by Christian Weber show that the chemokine receptor CXCR4 protects the integrity of arterial walls, and define a new mechanism that restricts the deleterious accumulation of cholesterol in atherosclerotic plaques.

Atherosclerosis is characterized by the build-up of fat-rich deposits on the inner surfaces of the endothelial that form the walls of the blood vessels. The presence of these atherosclerotic "plaques" leads to a chronic inflammation reaction, which can ultimately result in constriction of the vessel and the obstruction of blood flow in major arteries. Research teams led by Professor Christian Weber, Director of the Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases (IPEK) at the LMU Medical Center, have long focused their efforts on understanding the molecular mechanisms that underlie the pathogenesis and progression of the disorder. In two new studies, which appear in the journal Circulation, he and his colleagues now describe two previously unknown mechanisms that help to retard the formation of .

The CXCL12/CXCR4 signal relay

In a project funded by the European Research Council, Weber is investigating the contribution of a class of signal proteins known as chemokines to the pathogenesis of atherosclerosis. Chemokines are small proteins released by various types of immune cells, which interact with specific found on the surfaces of other cells and modulate their function. One of the new papers is devoted to the action of the chemokine CXCL12. Binding of CXCL12 by its receptor CXCR4 plays a significant role in controlling the recruitment of to sites of tissue inflammation. The results reported demonstrate that the interaction between CXCL12 and CXCR4 serves to inhibit the development of atherosclerotic plaques. "We have shown, for the first time, that activation of the chemokine receptor CXCR4 in endothelial cells limits the progression of atherosclerosis," Weber says.

The researchers investigated the role of the signaling pathway by specifically inducing the deletion of the gene for the receptor in either the of the arteries or in the underlying smooth-muscle cells. In a mouse model, they found that the resulting depletion of the protein in either cell type stimulated the formation of atherosclerotic deposits. "As the amount of activated receptor falls, the more permeable the vessel wall becomes," as Dr. Yvonne Döring, first author of the paper, explains. This in turn enables pro-inflammatory cells to migrate into the underlying tissues. Taken together, these observations imply that CXCR4 is essential for maintenance of the integrity of the endothelial cell layer. In addition, loss of the receptor in smooth-muscle cells altered their character and reduced their contractile responses. Subsequent analyses of variants of naturally occurring CXCR4 gene variants in humans confirmed that reduced expression of the receptor is indeed associated with increased risk for coronary heart disease.

Cholesterol efflux and the MC1-R pathway

In a further study carried out at the IPEK, Professor Sabine Steffens and Dr. Petteri Rinne (who is now at Turku University in Finland) identified a novel function of the receptor MC1-R. MC1-R is best known for its role in activating synthesis of the pigment melanin in the skin, which acts as an endogenous sunscreen and protects against the mutagenic effects of UV radiation. However, the receptor has a variety of other functions. For example, it is thought to be involved in the regulation of inflammatory responses, which raises the question of whether it too might play a role in atherosclerosis. "MC1-R is expressed on the surface of macrophages," says Steffens (macrophages are the immune system's waste-disposal service; they ingest and dispose of dead and dying cells and other debris), "and we have now shown that it regulates so-called reverse cholesterol transport in these cells." Specifically, the study demonstrates that activation of MC1-R promotes the extrusion of excess cholesterol from the macrophages found within atherosclerotic lesions, and actively prevents its re-uptake. Conversely, inhibition of the MC1-R signal pathway stimulates the transport of cholesterol into macrophages.

These findings imply that, like CXCR4, MC1-R also inhibits the development of atherosclerosis. Excessive uptake of cholesterol converts macrophages into so-called foam cells, which are known to contribute to the inflammation reactions within . This in turn increases the risk that plaques may rupture and obstruct blood-flow, which can lead to a heart attack or a stroke.

Explore further: New PET radiotracer identifies inflammation in life-threatening atherosclerosis

More information: Yvonne Döring et al. Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity: Evidence from Mouse and Human Studies, Circulation (2017). DOI: 10.1161/CIRCULATIONAHA.117.027646

Petteri Rinne et al. Melanocortin 1 Receptor Signaling Regulates Cholesterol Transport in Macrophages, Circulation (2017). DOI: 10.1161/CIRCULATIONAHA.116.025889

Related Stories

New PET radiotracer identifies inflammation in life-threatening atherosclerosis

March 1, 2017
In the featured article of the March 2017 issue of The Journal of Nuclear Medicine, researchers demonstrate that a new positron emission tomography (PET) radiotracer, gallium-68 (Ga-68)-pentixafor, can quickly and non-invasively ...

Monocyte migrations

February 19, 2013
LMU researchers led by Christian Weber have, for the first time, elucidated how cells that promote the development of atherosclerosis find their way to the blood vessel wall, where they stimulate the formation of obstructive ...

Tailored intervention in acute and chronic inflammation

April 6, 2017
Signal molecules called chemokines often work in tandem to recruit specific sets of immune cells to sites of tissue damage. A systematic analysis of their interactions by researchers from Ludwig-Maximilians-Universitaet (LMU) ...

Promising and perilous? The ambivalent role of the CXCL12/ CXCR4 axis in heart repair

November 30, 2011
The chemokine CXCL12 acts as a chemical signal which mobilizes hematopoietic and other types of stem cells to leave the bone marrow and enter the circulation. Secretion of CXCL12 also guides these cells to sites at which ...

Endogenous peptide lowers cholesterol

January 19, 2017
Cells of the innate immune system that play an important role in development of atherosclerosis contain a protein that reduces levels of cholesterol in mice – and thus helps to inhibit or mitigate the disease.

Atherosclerosis—a short cut to inflammation

February 10, 2016
The enzyme Dicer processes RNA transcripts, cutting them into short segments that regulate the synthesis of specific proteins. An Ludwig-Maximilians-Universitaet (LMU) in Munich team has shown that Dicer promotes the development ...

Recommended for you

New drugs could reduce risk of heart disease when added to statins

September 20, 2018
New drugs that lower levels of triglycerides (a type of fat) in blood could further reduce the risk of heart attack when added to statins. These new drugs, which are in various stages of development, could also reduce blood ...

Mediterranean-style diet may lower women's stroke risk

September 20, 2018
Following a Mediterranean-style diet may reduce stroke risk in women over 40 but not in men—according to new research led by the University of East Anglia.

Can a common heart condition cause sudden death?

September 20, 2018
About one person out of 500 has a heart condition known as hypertrophic cardiomyopathy (HCM). This condition causes thickening of the heart muscle and results in defects in the heart's electrical system. Under conditions ...

Inflammation critical for preventing heart attacks and strokes, study reveals

September 19, 2018
Inflammation, long considered a dangerous contributor to atherosclerosis, actually plays an important role in preventing heart attacks and strokes, new research from the University of Virginia School of Medicine reveals.

People who walk just 35 minutes a day may have less severe strokes

September 19, 2018
People who participate in light to moderate physical activity, such as walking at least four hours a week or swimming two to three hours a week, may have less severe strokes than people who are physically inactive, according ...

Effective drug delivery to heart with tannic acid

September 18, 2018
Typical methods of drug delivery to the heart require surgical procedures involving incisions in the chest wall and bones. To efficiently treat cardiovascular and related vascular diseases without surgery, a KAIST research ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.