Fight Aging!

Macrophage dysfunction is the crucial central issue in atherosclerosis, the ultimately fatal buildup of fatty lesions in blood vessel walls. Macrophages are the innate immune cells responsible for clearing out inappropriate lipid deposition in blood vessel walls, returning those lipids to the bloodstream. With age, rising levels of inflammatory signaling and toxic, oxidized lipids cause macrophages to falter at this task. Macrophages in the vicinity of growing atherosclerotic lesions become inflammatory foam cells and die, adding to the lesion while attracting more macrophages to the same fate.

The best approach to a cure for atherosclerosis is to intervene in macrophage function, but this is so far an underfunded and underappreciated part of the field. If macrophages can be made resilient to the factors that force them into dysfunction, then they should return to the task at hand, functioning as they did in youth, and reverse the development of atherosclerotic lesions. There are, unfortunately, few research programs focused on this goal, and only a couple of biotech companies (such as Underdog Pharmaceuticals and Repair Biotechnologies) undertaking relevant preclinical programs. So it is always interesting to see a greater diversity of progress on this front, even if the work here appears to be somewhat removed from the root causes of macrophage dysfunction, and is focused on downstream issues within cell metabolism.

Dysregulated oxalate metabolism is a driver and therapeutic target in atherosclerosis

Despite significant advances in diagnosis, drug development, and medical treatment, cardiovascular diseases (CVDs) remain a leading cause of death worldwide. Atherosclerosis, the underlying cause of most CVDs, is a chronic disease of the arteries arising from imbalanced lipid metabolism, a maladaptive immune response, and dysregulated redox homeostasis. While the association between altered lipid metabolism and CVDs is well established, recent evidence indicates that dysregulated metabolism of specific amino acids plays an important role in the pathogenesis of atherosclerosis. Among all amino acids, lower circulating glycine is emerging as a common denominator in CVDs and related metabolic comorbidities, including coronary heart disease, myocardial infarction, obesity, type 2 diabetes (T2D), metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). While numerous studies reported lower circulating glycine in cardiometabolic diseases, the contribution of impaired glycine metabolism to the development of atherosclerosis remains unclear.

Glycine is the simplest, nonessential amino acid and is synthesized primarily in the liver from serine, threonine, alanine, and glyoxylate. Impaired biosynthesis of glycine in atherosclerosis was suggested by evidence of a decreased glycine/serine ratio in plasma from patients with unstable atherosclerotic plaques. Furthermore, transcriptomics of human and mouse livers revealed suppression of genes driving glycine biosynthesis in NAFLD, predominantly alanine-glyoxylate aminotransferase (AGXT). AGXT is expressed primarily in the liver where it catalyzes glycine biosynthesis from alanine and glyoxylate. Functional deficiencies of AGXT lead to accumulation of glyoxylate, which is rapidly converted to oxalate. Whereas limited literature proposed that dysregulated oxalate metabolism is linked to CVDs, the role of this metabolic pathway in the pathogenesis of atherosclerosis has not been studied yet.

In this study, using targeted metabolomics, we identified decreased ratios of glycine to its precursors or related metabolites, serine, threonine, and oxalate, in patients with coronary artery disease (CAD). As found in patients with CAD, the glycine/oxalate ratio was significantly decreased in atherosclerotic Apoe-/- mice that showed suppression of hepatic AGXT. Utilizing genetic and dietary approaches to manipulate oxalate in Apoe-/- mice combined with studies in isolated macrophages, we demonstrate that increased oxalate exposure drives accelerated atherosclerosis in relation with dysregulated redox homeostasis, an increased inflammatory response, and enhanced hypercholesterolemia. The therapeutic potential of targeting dysregulated oxalate metabolism in atherosclerosis was studied using adeno-associated virus (AAV)-mediated overexpression of AGXT in Apoe-/- mice that showed lower oxidative stress, inflammation, and atherosclerosis. Thus, by studying impaired glycine metabolism in patients and mice with atherosclerosis and using mouse models to manipulate oxalate, we identified dysregulated oxalate metabolism via suppressed AGXT as a driver and therapeutic target in atherosclerosis.