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Each year, almost a third of deaths worldwide are attributed to CVD, accounting for 17.9 million deaths according to the World Health Organization (WHO). These figures place CVD as the world’s leading cause of death, surpassing the annual death toll attributed to other common causes of death including all kinds of cancer combined, diabetes, and chronic obstructive pulmonary disease (COPD).
85% of CVD deaths are caused by heart attacks and strokes. The formation build-up of fatty deposits in the arteries, known as atherosclerosis, causes the arteries to narrow, making blood clots more likely. Often, atherosclerosis presents itself clinically as a thrombosis, where a blot clot forms within a blood vessel. This condition is considered to be the major underlying cause of heart attacks and strokes.
While atherosclerosis is known to play a vital role in CVD it often develops without initial symptoms. A person may have the condition for years without any warning signs. Scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, recognized the potential value of developing a new diagnostic tool for indicating the presence of atherosclerosis.
ALDH4A1’s Role in Atherosclerosis
Dr. Almudena Ramiro, who led the recent study at the CNIC, outlined the rationale he and his team had for investigating potential markers of atherosclerosis, “we know that atherosclerosis includes an immunological component and that the innate and adaptive immune systems are both involved in the origin and progression of this disease.”
The team at CNIC has identified the mitochondrial protein ALDH4A1 as an autoantigen that is involved in atherosclerosis. In their study, published in Nature, the team describes how mice lacking the low-density lipoprotein receptor (LDLR-/-) were monitored as they were fed a high-fat diet.
The scientists were able to characterize the antibody response triggered by atherosclerosis, which developed as a result of the high-fat diet. The study’s findings highlighted that a family of specific antibodies in the germinal centers are associated with atherosclerosis. Germinal centers are the location of B cell antibody diversification, where they differentiate into plasma cells and high-affinity memory B cells.
The team analyzed sequences of over 1,700 antibody genes and found that a distinct antibody repertoire was produced by mice with atherosclerosis. Further analysis revealed that the antibody A12, in particular, can recognize plaques in both the atherosclerosis-prone mice as well as in samples taken from human patients with atherosclerosis in the carotid arteries. A12 was found to recognize A1 (ALDH4A1), a mitochondrial protein, identifying it as an autoantigen for atherosclerosis.
The results show that ALDH4A1 builds up in the plaques that characterize atherosclerosis. Also, the protein was found in elevated levels in the plasma of atherosclerosis-prone mice and human patients with carotid atherosclerosis. The study’s findings implicate ALDH4A1 as a potential biomarker for carotid atherosclerosis.
When A12 antibodies were introduced to the atherosclerosis-prone mice the team found that plaque formation was related and the plasma levels of free cholesterol and LDL were reduced. These results demonstrate that anti-ALDH4A1 antibodies could possibly be used in future therapies for atherosclerosis.
Overall, the work conducted by the team at CNIC is invaluable to deepening our knowledge of the underlying mechanisms of atherosclerosis, and it offers a window to potential future diagnostic and therapeutic approaches to CVD.