A new approach to treating heart disease

A research team was able to describe the process underlying the contribution of a certain protein in blood vessel cells to the development of vascular and cardiovascular diseases.

Researchers discover a new way to treat cardiovascular disease.

Vascular and cardiovascular diseases are strongly influenced by a particular protein present in the cells of blood vessels. Researchers have found that the presence of too many “thromboxane A2 receptors” also prevents the growth of new blood vessels. The fundamental process was finally explained by a research team led by Martin Luther University Halle-Wittenberg (MLU). The research, which was published March 3 in the journal Arteriosclerosis, Thrombosis and Vascular Biology, may lead to the creation of new treatments for cardiovascular diseases.

The formation of blood vessels is a complex process. “The different processes of inhibition and stimulation must work together like cogs in a wheel. Certain cells in the blood vessels, called endothelial cells, play a key role in this process, regulating the exchange between blood and tissues,” says lead author Professor Ralf Benndorf, pharmacologist at MLU’s Institute of Pharmacy. .

The researchers studied a protein important for haemostasis: the thromboxane A2 receptor, which causes platelets to adhere and contributes to the constriction of blood vessels.

“We already knew that patients with cardiovascular disease and pathological changes in their blood vessels had increased numbers of these receptor proteins in their blood vessels,” Benndorf adds. However, it was unclear whether this finding had any clinical relevance, in other words, whether there was a link between this increased number and the development of the disease.

The researchers were able to fill this gap by deciphering a complicated interaction triggered by this receptor protein. Experiments show that the problem occurs when the protein is present in blood vessels in excessive amounts.

“The receptor triggers the production of the pro-inflammatory enzyme cyclooxygenase-2. This enzyme in turn produces messenger substances that activate the receptor,” says Benndorf. This constant, self-reinforcing cycle of activation of the receptor in blood vessel cells means that the cells have difficulty forming new blood vessels. It also significantly restricts endothelial cell function.

“Under the microscope, you can see how tense the cells really are if there’s a higher density of receptors,” Benndorf says.

It is still unclear why the protein occurs more frequently in the blood vessel cells of people with cardiovascular disease.

“However, it is a promising biomarker and could be an attractive target for pharmacological interventions,” says Benndorf. Harmful effects in cells could be reversed using substances that block the action of the receptor or enzyme.

“Receptor inhibition could therefore represent a new treatment option for patients who have elevated levels of the thromboxane A2 receptor in their blood vessels. This could improve vascular function and regeneration,” says Benndorf.

The first drugs targeting the protein are already in clinical trials for use in other applications.

“Even though the substances have not yet been approved, clinical trial results indicate that they are well tolerated and may improve vascular function,” Benndorf says. Current investigations have taken place in cell cultures and in laboratory animal studies. Further study of the potential therapeutic benefit in preclinical disease models is needed before they can be tested or used in humans.

The work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) and by the European Regional Development Fund (ERDF).

Reference: “A thromboxane A2 Receptor-driven COX-2-dependent feedback loop that affects endothelial homeostasis and angiogenesis” by Robert Eckenstaler, Anne Ripperger, Michael Hauke, Markus Petermann, Sandra A. Hemkemeyer, Edzard Schwedhelm, Süleyman Ergün, Maike Frye , Oliver Werz, Andreas Koeberle, Heike Braun and Ralf A. Benndorf, March 3, 2022, Arteriosclerosis Thrombosis and vascular biology.
DOI: 10.1161/ATVBAHA.121.317380