Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with atherosclerosis at their core. Despite advances in prevention and drug therapy, the incidence of CVDs and related deaths continues to rise. Therefore, prevention and treatment are necessary at the earliest stages of CVD – before symptoms appear.
The risk of atherosclerosis is typically assessed by indicators such as cholesterol levels, blood pressure, smoking status, and age. However, this approach does not allow for early detection. Current drugs target known mechanisms – lipid metabolism and inflammation – yet even with such therapy, many patients retain a high residual cardiovascular risk.
A new approach involves studying the gut microbiota. Metabolites produced through its interaction with the body can play an essential role in the development of CVDs. So far, only a few such compounds have been linked to late stages of atherosclerosis, making the search for metabolites involved in early stages particularly important.
Imidazole Propionate (ImP) – A Microbial Metabolite Linked to Atherosclerosis
To identify metabolites influencing atherosclerosis, Spanish scientists studied mice predisposed to the disease. The animals were fed a high-cholesterol diet that induced atherosclerosis. Antibiotic treatment, which suppressed the microbiota, slowed disease progression – indicating the involvement of gut bacteria in atherosclerosis.
Metabolomic analysis revealed that plasma composition changed depending on diet and microbiota. The researchers confirmed the known association between trimethylamine N-oxide (TMAO) and atherosclerosis.
They also identified a new metabolite, ImP, whose levels increased with a high-cholesterol diet and were strongly associated with the development of atherosclerosis. ImP concentration depended on microbiota composition, particularly on the abundance of Escherichia, Shigella, and Eubacterium. Further studies are needed to identify the specific bacterial strains that produce ImP.
ImP as a Marker of Early Atherosclerosis in Humans
A study of asymptomatic volunteers showed that blood levels of ImP correlated with subclinical atherosclerosis. In the PESA cohort (Progression of Early Subclinical Atherosclerosis, 400 participants), ImP levels were elevated in those with early signs of atherosclerosis and correlated with the extent of vascular damage. These findings were confirmed in an independent cohort of 1,844 participants.
ImP levels were influenced by lifestyle and microbiota, as they were lower in individuals following a Mediterranean diet and eating breakfast regularly, and higher in those with increased Veillonella and Acidaminococcus, and lower Erysipelotrichaceae and Coriobacteriaceae.
ImP was associated with an unfavorable cardiometabolic profile – higher glucose, inflammation, obesity, dyslipidemia, and hypertension. Even after adjusting for traditional risk factors, ImP remained an independent predictor of atherosclerosis and improved risk prediction compared with classic biomarkers such as LDL and high-sensitivity C-reactive protein (hs-CRP).
Notably, the highest ImP levels were found in individuals with metabolically active atherosclerosis associated with systemic inflammation and bone marrow activation, which makes ImP a promising marker of early and active atherosclerosis.
ImP Induces Atherosclerosis Without Altering Cholesterol Levels
In experiments on mice predisposed to atherosclerosis, adding ImP to drinking water accelerated the development of aortic plaques without affecting cholesterol or glucose levels.
After eight weeks of ImP administration, mice showed increased numbers of inflammatory monocytes and T-helper cells (Th1 and Th17). Aortic tissue analysis revealed an increased presence of immune cells, fibroblasts, and endothelial cells, as well as a greater accumulation of T cells and inflammatory macrophages in the plaques.
The effect of ImP was markedly reduced in mice lacking T and B cells. Thus, ImP promotes atherosclerosis in predisposed mice by activating immune responses independently of cholesterol concentration.
ImP Activates Inflammation Through the mTOR Pathway
Gene expression analysis of aortic tissues showed that ImP enhanced inflammatory pathways in macrophages and fibroblasts. Genes associated with homeostasis were downregulated, while those involved in lipid metabolism, inflammation, and macrophage activation were upregulated.
Cell culture experiments demonstrated that ImP activates mouse embryonic fibroblasts, stimulating the production of monocyte chemoattractant protein-1 (MCP-1), which promotes monocyte recruitment and plaque formation. ImP also induced activation and inflammatory pathways in macrophages, but not in endothelial cells, suggesting that macrophages and fibroblasts are its primary targets.
ImP activated the mTOR pathway in macrophages and fibroblasts, as indicated by elevated p-S6 protein levels. The mTOR inhibitor rapamycin blocked ImP-induced TNF production. In mice treated with ImP for eight weeks, p-S6 levels were increased in macrophages. Deletion of the Raptor gene, required for mTOR function, abolished the atherogenic effect of ImP.
Thus, ImP promotes atherosclerosis by triggering mTOR-dependent inflammatory responses in myeloid cells.
ImP Acts Through the I1R Receptor, and Its Blockade Protects Against Atherosclerosis
ImP activates inflammatory pathways in macrophages and fibroblasts through the imidazoline receptor I1R. ImP elevated p-S6 and TNF levels, while the I1R antagonist AGN192403 completely abolished these effects. AGN192403 also inhibited ImP-induced activation of the mTOR pathway. Deletion of the I1R gene in myeloid cells prevented ImP-induced atherosclerosis.
To assess the therapeutic potential of AGN192403, researchers administered ImP together with AGN192403 in drinking water to mice predisposed to atherosclerosis. Pharmacological blockade of I1R did not affect cholesterol or ImP levels but prevented inflammatory cytokine production, immune cell accumulation in the aorta, and plaque formation.
Blocking the ImP–I1R Axis Prevents Atherosclerosis Progression
In mice predisposed to atherosclerosis, a high-cholesterol diet increased ImP levels and triggered the development of plaque. Treatment with the I1R inhibitor AGN192403 for four weeks reduced disease progression in both males and females without altering plasma ImP. AGN192403 decreased plaque size and complexity and suppressed immune cell activation without affecting cholesterol levels.
Thus, blocking the ImP–I1R axis protects against atherosclerosis by reducing inflammation independently of cholesterol levels, opening a new avenue for therapeutic intervention.
Conclusion
Atherosclerosis develops silently for years and is difficult to detect early. Previously, ImP was associated mainly with late-stage cardiovascular disease. This study demonstrated that ImP is linked to early atherosclerosis in humans and drives its progression in mice independently of cholesterol.
ImP activates inflammatory pathways in macrophages and fibroblasts, and to a lesser extent in endothelial cells, leading to immune cell infiltration, vascular inflammation, and formation of unstable plaques.
ImP acts through the I1R receptor, initiating an mTOR-dependent inflammatory response in myeloid cells. Pharmacological blockade of I1R completely prevents the atherogenic effects of ImP.
Blocking I1R reduces inflammation and slows plaque growth without affecting cholesterol levels, making the ImP–I1R axis a promising therapeutic target to complement existing treatments and reduce residual cardiovascular risk.
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Reference
Imidazole propionate is a driver and therapeutic target in atherosclerosis
