In atherosclerosis, cholesterol and other fatty deposits build up around the inner walls of an artery, creating a plaque that restricts blood flow. Plaques pose a double risk — they can detach from the artery causing a blood clot or lead to a heart attack or stroke.
The problem is that plaques form gradually over years, without any symptomatic warning signs. The key to earlier interventions is the identification of biomarkers to alert physicians to the presence of atherosclerosis before it’s too late. In the United States, over 600,000 people die of heart disease every year, representing 1 in 4 deaths.
In a recent publication in Nature, scientists have made an important connection between atherosclerosis and the immune system, leading to the discovery of a new biomarker for the condition.
One of the authors, Almudena Ramiro, said: "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."
Ramiro and colleagues demonstrated that in atherosclerosis, the immune system recognizes a mitochondrial protein called ALDH4A1 as an autoantigen, producing antibodies against it.
"ALDH4A1 is recognized by the protective antibodies produced during atherosclerosis, making it a possible therapeutic target or diagnostic marker for this disease," said Ramiro.
Diving deeper into their hypothesis that ALDH4A1 antibodies could represent a viable diagnostic biomarker, the team performed a series of experiments in transgenic mice on a high-fat diet. They studied the immune repertoire of antibodies produced by these mice during atherosclerosis using high-throughput screening and gene sequencing.
"Analysis of the sequences of more than 1700 antibody genes showed that mice with atherosclerosis produced a distinct antibody repertoire. The production of these antibodies allowed us to study their targets (their antigen specificity) and their functional properties," said study collaborator Hedda Wardemann.
"The study shows that ALDH4A1 accumulates in plaques and that its plasma concentration is elevated in the atherosclerosis-prone mice and in human patients with carotid atherosclerosis, establishing ALDH4A1 as a possible biomarker of the disease," added Ramiro.
In another exciting finding, the team showed that ALDH4A1 antibodies could also be used as a preventative treatment or therapeutic. Administering these antibodies to mice delayed the development of plaques and also suppressed levels of circulating free cholesterol.
"These results broaden our knowledge of the humoral response during atherosclerosis and highlight the potential of ALDH4A1 as a new biomarker and of A12 as a therapeutic agent for this disease," concludes Ramiro.