Biological Glue Provides Clues About Cardiovascular Diseases

University of Virginia School of Medicine scientists have found important answers about strokes, heart attacks and cardiovascular diseases by probing the biological glue our bodies create to protect us from those deadly dangers.

The researchers, led by Mete Civelek, PhD, wanted to better understand factors that influence our risk for cardiovascular diseases such as atherosclerosis, the hardening of the arteries. Atherosclerosis is characterized by the buildup of fatty plaques in our blood vessels. When these plaques form, our bodies build fibrous caps over them to keep them from breaking loose and causing heart attacks and strokes.

Civelek and his team thought that the scaffolding our bodies build over these plaques might contain important clues that could improve our understanding of cardiovascular diseases, the leading cause of death around the world. And by taking a clever approach, the scientists were able to obtain important new insights that could advance the development of lifesaving treatments. 

We combined two decades of human genetics findings and a unique resource of smooth muscle cells, an important component of arteries where the plaques develop. We discovered that our genetic makeup impacts the ways smooth muscle cells secrete proteins that provide strength to plaques and prevent them from rupturing and causing heart attacks and strokes."

Mete Civelek, PhD, UVA's Center for Public Health Genomics and the Department of Biomedical Engineering

Vital Cellular Glue

To construct the protective scaffolding over the potentially deadly plaques, smooth muscle cells that line our blood vessels secrete what is known as "extracellular matrix" – a fibrous, glue-like material rich in proteins. Civelek and his team measured these proteins, and related proteins, in smooth muscle cells collected from 123 heart transplant donors. The scientists were then able to work backward, essentially, to ­­identify genes that made those proteins.

Doing this let the scientists identify 20 locations on our chromosomes that house genes that influence the production of the critical proteins. It also let them pinpoint a naturally occurring gene variation that puts certain people at higher risk for hardening of the arteries, as well as identify types of proteins that contribute to our cardiovascular risk. Doctors may be able to leverage the new insights to identify patients at greatest risk of having the plaques break free and cause heart attacks or strokes, the UVA researchers say.

The findings also shed important light on why the efforts of the smooth muscle cells sometimes are beneficial and sometimes are harmful. That information will be a great asset to researchers seeking to develop new treatments for atherosclerosis and cardiovascular diseases, Civelek says.

"We identified one protein, LTBP1, that we think plays an important role in plaque stability," he said. "We will continue to study if this protein can be a beneficial therapeutic target and hope to translate our findings to patient care soon." 

Findings Published

The researchers have published their findings in the scientific journal Arteriosclerosis, Thrombosis, and Vascular Biology. The research team consisted of Rédouane Aherrahrou, Ferheen Baig, Konstantinos Theofilatos, Dillon Lue, Alicia Beele, Tiit Örd, Minna U. Kaikkonen, Zouhair Aherrahrou, Qi Cheng, Saikat Ghosh, Santosh Karnewar, Vaishnavi Karnewar, Aloke Finn, Gary K. Owens, Michael Joner, Manuel Mayr and Civelek. The researchers have no financial interest in the work.

The research was supported the American Heart Association, postdoctoral fellowship 18POST33990046; the University of Eastern Finland; the German Centre for Cardiovascular Research; the CORONA Foundation, grant S0199/10097/2023; Transformational Project Award 19TPA34910021; the National Institutes of Health, grant R21HL135230 and. R01 HL155165; the Academy of Finland, grants 333021 and 335973; the European Research Council Horizon 2020 Research and Innovation Programme, grant 802825; the Finnish Foundation for Cardiovascular Research; the Sigrid Jusélius Foundation; and Foundation Leducq, International Network of Excellence Awards 12CVD02, 18CVD02 and 22CVD04 and its Junior Investigator Award.

 UVA's Department of Biomedical Engineering is a joint program of the School of Medicine and the School of Engineering.

Source:
Journal reference:

Aherrahrou, R., et al. (2024). Secreted Protein Profiling of Human Aortic Smooth Muscle Cells Identifies Vascular Disease Associations. Arteriosclerosis, Thrombosis, and Vascular Biology. doi.org/10.1161/atvbaha.123.320274.

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