CARD8 protein could be novel atherosclerosis drug target

According to a new study, the Caspase activation and recruitment domain 8 (CARD8) protein regulates several inflammatory proteins implicated in atherosclerosis. One of the researchers, Geena Paramel, said their findings show entirely new functions for CARD8 and could be important in developing treatments for atherosclerosis and other inflammatory diseases.

Atherosclerosis is the hardening of arteries due to chronic inflammation in the vessel walls. It is the primary cause of most cardiovascular diseases. According to the researchers, several proteins and pro-inflammatory cytokines are involved in the progression of atherosclerosis. The overexpression of mRNA encoding the CARD8 protein – a component of the innate immune system – has also been associated with the disease, but its role in the inflammation was unknown.

In this study, researchers sought to investigate whether CARD8 regulates the expression of pro-inflammatory cytokines and chemokines in the endothelial cells of arteries. Taking sections of human atherosclerotic lesions and non-atherosclerotic arteries, the team, led by Professor Allan Sirsjö at Örebro University’s Cardiovascular Research Centre (CVRC), Sweden, immunostained them for CARD8 protein. According to the team, expression of CARD8 was correlated to mediators of inflammation in atherosclerotic lesions and the expression of inflammatory genes such as CXCL1, CXCL6 and PDGF-A.

To better understand the function of CARD8, the team then knocked it out in human umbilical vein endothelial cells (HUVECs). They reported that the knock-down of CARD8 mRNA in HUVECs significantly altered proteins involved in inflammatory response, such as CXCL1, CXCL6, PDGF-A, MCP-1 and IL-6. From this the team concluded that CARD8 regulates the expression of cytokines and chemokines in endothelial cells and atherosclerotic lesions – and suggested that CARD8 plays a significant role in endothelial activation.

Their in vitro results have been confirmed in samples from a group of individuals with atherosclerosis.

“These findings are significant in that they may be key in the development of upcoming drugs for atherosclerosis. In the future, we may be able to use more targeted drugs against CARD8 in atherosclerosis,” said Karin Franzén, docent in biomedicine at Örebro University and contributing authors in the study.

Aside from its role in atherosclerosis, CARD8 plays a key role in the inflammatory processes that are vital for tumour development and genetic variations in the CARD8 gene have also been associated with altered levels of inflammatory proteins in the body. Therefore, the team suggest their findings may be “significant for several other inflammation-related diseases”.

The scientists are currently continuing their work, mapping the role that CARD8 plays in inflammatory processes and also exploring how CARD8 affects other processes in cells.

The study was published in Scientific Reports.