Most people who arrive an a hospital in the wake of a first heart attack or stroke due to rupture of an unstable atherosclerotic plaque in the arteries do not have elevated LDL cholesterol. This is cholesterol attached to LDL particles, coming from the liver for delivery to the rest of the body. While high LDL cholesterol is recognized as, on balance across a population, contributing to the pace at which plaque grows, it is not the whole story. It is probably not the most important part of the story either, given than the well-established therapies to lower LDL cholesterol do not reliably regress plaque, and only slow its growth somewhat.
Researchers have in recent years searched for and uncovered a broad range of other mechanisms that contribute to plaque growth in animal models of atherosclerosis. This has led to various markers, such as circulating Lp(a), that correlate with atherosclerotic plaque and consequent cardiovascular disease in human study populations. A number of biotech and pharmaceutical companies are working on the development of therapies to target these mechanisms, near all of which only produce a slowing of plaque growth when tested in animal models.
In today's open access paper, researchers propose a novel way in which the gut microbiome can contribute to the creation and growth of atherosclerotic plaque in blood vessel walls. They point to a metabolite generated by microbes in the gut, imidazole propionate, and demonstrate that it can be used to promote plaque growth in animal models of atherosclerosis. Like all mechanisms promoting plaque growth, this appears to negatively affect the macrophage cells that are drawn to a plaque and attempt to repair the damage, ensuring that more of these cells are incapacitated and killed by the toxic plaque environment.
Imidazole propionate is a driver and therapeutic target in atherosclerosis
Atherosclerosis is the main underlying cause of cardiovascular diseases. Its prevention is based on the detection and treatment of traditional cardiovascular risk factors. However, individuals at risk for early vascular disease often remain unidentified. Recent research has identified new molecules in the pathophysiology of atherosclerosis, highlighting the need for alternative disease biomarkers and therapeutic targets to improve early diagnosis and therapy efficacy.
Here, we observed that imidazole propionate (ImP), produced by microorganisms, is associated with the extent of atherosclerosis in mice and in two independent human cohorts. Furthermore, ImP administration to atherosclerosis-prone mice fed with chow diet was sufficient to induce atherosclerosis without altering the lipid profile, and was linked to activation of both systemic and local innate and adaptive immunity and inflammation.
Specifically, we found that ImP caused atherosclerosis through the imidazoline-1 receptor (I1R, also known as nischarin) in myeloid cells. Blocking this ImP-I1R axis inhibited the development of atherosclerosis induced by ImP or high-cholesterol diet in mice. Identification of the strong association of ImP with active atherosclerosis and the contribution of the ImP-I1R axis to disease progression opens new avenues for improving the early diagnosis and personalized therapy of atherosclerosis.
View the full article at FightAging
