Atherosclerosis is the development of fatty plaques in blood vessel walls, formed of damaged lipids and the debris of dead cells. Once developed in earnest, these become localized areas of chronic inflammation. Inflammatory signaling continually calls in macrophages that attempt to clear up the damage, become overwhelmed, and add their remains to the growing mass. In the late stage of the condition, blood vessels are narrowed and weakened, and the plaques become unstable, prone to rupture. Here, researchers show that cells found in unstable fatty plaque are distinct from those in stable plaque. They look more like cancer cells or activated immune cells in the operation of their metabolism.
This is interesting in light of the recent discovery that growth and instability in atherosclerotic plaque is driven in part by the senescence of macrophages. The macrophages attempting to clean up the plaque become senescent as they are overwhelmed by damaged lipids that they cannot effectively break down. They become foam cells as they are loaded with lipids, and the foam cells become senescent in response to their own damaged state and the plaque environment. Senescent cells secrete signals that promote inflammation and disruptive remodeling of surrounding tissue structure, and are different from normal cells in other ways as well. Removing just senescent macrophages can stabilize plaque and slow or reverse the progression of atherosclerosis. This is something to think about while looking over the results here.
Atherosclerotic plaques form over a long time by a focal accumulation of lipids, immune cells, and smooth muscle cells in the arterial wall and plaques that rupture can cause acute cardiovascular events, such as myocardial infarction and stroke. Rupture-prone, high-risk plaques are associated with clinical symptoms and characterized by histological evidence of vulnerability and a high inflammatory burden. While this knowledge has advanced considerably over the past few years, our understanding of the metabolic processes within plaques in this inherently metabolic disorder has been lagging behind.
Emerging research has shown that cell metabolism and the inflammatory response are tightly intertwined. Macrophages, abundantly found in atherosclerotic plaques, and other leucocytes, change their metabolism according to their tasks in the immune response. Activated leucocytes change to a predominantly anabolic metabolism by upregulating pathways, such as glycolysis, the pentose-phosphate pathway (PPP), and glutaminolysis, to provide the necessary energy to enable their activation and proliferation. In contrast, catabolic pathways, such as fatty acid oxidation (FAO), are downregulated in these cells. Recently, it has been shown that overutilization of glucose is crucial for blood monocytes and in vitro differentiated macrophages from patients with coronary artery disease (CAD) to mount a destructive inflammatory response. Yet, it remains to be determined whether such an interconnection between cellular metabolism and the inflammatory response is present in human atherosclerotic plaques.
Recent studies have challenged the established concept of the vulnerable atherosclerotic plaque and call for improved methods for identification of the high-risk plaque. Plaque metabolomics might be able to provide a largely unexplored layer of functional characterization of high-risk lesions and thus add value to future risk stratification strategies and novel therapeutic approaches. Metabolic profiling of atherosclerotic tissues has so far focused on comparing lipid metabolite levels in different parts of the same plaque or to plaque adjacent intimal thickenings without being able to produce clear biological insights of clinical significance.
A more clinically relevant approach is to distinguish high- from low-risk plaques according to their metabolic profile. Therefore, we assessed metabolite profiles of 159 highly stenotic carotid atherosclerotic plaques isolated from patients with or without symptoms. We show that high-risk plaques, characterized as being symptomatic, vulnerable by histology, and inflamed with elevated inflammatory mediators, had a specific metabolite signature, distinct from the metabolite profile of low-risk plaques. These data highlight a previously unappreciated role of cellular metabolism in the high-risk plaque and as a discriminating feature from low-risk plaques, indicating that metabolic pathways could be targeted to treat and identify high-risk atherosclerotic plaques.