Protein could extend saphenous vein graft durability

Scientists show that CRP3, normally produced in arteries, is expressed in saphenous vein grafts following coronary artery bypass surgery. The finding suggests that this molecule participates in adaptation to the increased blood flow and pressure resulting from arterialization.

By André Julião in Campos do Jordão (Brazil)  |  Agência FAPESP –  A group of researchers based in Brazil and the United Kingdom are looking for ways to increase the durability of the saphenous vein grafts used in coronary artery bypass surgery to restore blood flow to the heart. Coronary artery blockage can lead to a heart attack if left untreated.

The project is funded by FAPESP under its program for São Paulo Researchers in International Collaboration (SPRINT).

One of the keys to preventing saphenous vein graft failure (which requires a second intervention) may be CRP3 (cysteine and glycine-rich protein 3), a protein normally produced by arteries. Researchers at the Heart Institute (INCOR) of Hospital das Clínicas, the general hospital run by the University of São Paulo’s Medical School (HC-FMUSP) in Brazil, discovered that saphenous vein grafts begin producing CRP3 following the operation and concluded that this was a mechanical response to higher pressure, as the flow of blood through the arterialized graft is greater than through the vein in its original location in the leg.

This adaptive response, however, is not sufficient to withstand the increased blood flow for a long time. The vessel eventually develops wall lesions, and in 50% of patients, obstructions appear between five and ten years later, requiring a second bypass surgery.

“Our aim is to modulate CRP3 or other proteins found to be important to this adaptation process, so that the durability of vein bypass grafts can be extended,” said Ayumi Aurea Miyakawa, a researcher at INCOR and principal investigator for the study.

A presentation on the study was delivered on September 11, 2019, to the 34th Annual Meeting of the Federation of Brazilian Societies for Experimental Biology (FeSBE), held with FAPESP’s support in Campos do Jordão (São Paulo State, Brazil).

Advances

Previous research by the group, demonstrating increased levels of vein graft CRP3 expression, was published in 2009. In another project funded by FAPESP, venous arterialization in rats genetically modified not to express CRP3 underperformed compared with venous arterialization in normal rats (in this case, a jugular vein graft was used). The findings were published in 2018 in the journal Clinical Science.

“Our hypothesis is that CRP3 participates in mechanotransduction, the process whereby cells sense and respond to mechanical stress. Human saphenous vein grafts produce the protein in an effort to cope with this stress,” Miyakawa said.

Protein chain

Miyakawa and her group are now investigating the role played by CRP3 in focal adhesions, protein complexes on the cell surface that anchor the cell to the extracellular matrix. Focal adhesions are involved in several biochemical processes, including the sensing of mechanical stress due to augmented blood flow.

In this venture, the Brazilians are partnering with a group led by Christoph Ballestrem, a professor at the University of Manchester in the UK.

Research by Ballestrem’s laboratory at Manchester has already shown the importance of other proteins in the response to mechanical stress. Vinculin and talin are present in focal adhesions and play a key role in the response to mechanical changes, binding to integrins (proteins that attach the cell cytoskeleton to the extracellular matrix) and sensing physical stimuli for conversion into biochemical signals.

“We’re showing that several proteins present in focal adhesions control different mechanical stress response modules. CRP3 and other proteins in the CRP family belong to a third module, which we hadn’t studied previously and is absolutely critical to mechanotransduction,” said Ballestrem, who presented his group’s research in the same session of the meeting.

For researchers, it is too early to start thinking about new treatments, but a deeper understanding of the mechanisms involved in mechanotransduction is essential to the development of novel therapeutic strategies.

“We’re endeavoring to elucidate these mechanisms through this collaboration,” Ballestrem said. “If we succeed, we’ll be able to manipulate them and thereby control cell behavior. In addition to extending saphenous vein graft durability, this could be important in novel treatments for fibrosis and cardiovascular diseases, among others.”