Imidazole propionate is a driver and therapeutic target in atherosclerosis

Annalaura Mastrangelo, Iñaki Robles-Vera, Diego Mañanes, Miguel Galán, Marcos Femenía-Muiña, Ana Redondo-Urzainqui, Rafael Barrero-Rodríguez, Eleftheria Papaioannou, Joaquín Amores-Iniesta, Ana Devesa, Manuel Lobo-González, Alba Carreras, Katharina R. Beck, Sophie Ivarsson, Anders Gummesson, Georgios Georgiopoulos, Manuel Rodrigo-Tapias, Sarai Martínez-Cano, Ivan Fernández-López, Vanessa Nuñez, Alessia Ferrarini, Naohiro Inohara, Kimon Stamatelopoulos, Alberto Benguría, Danay Cibrian, Francisco Sánchez-Madrid, Vanesa Alonso-Herranz, Ana Dopazo, Coral Barbas, Jesús Vázquez, Juan Antonio López, Alicia González-Martín, Gabriel Nuñez, Konstantinos Stellos, Göran Bergström, Fredrik Bäckhed, Valentín Fuster, Borja Ibañez and David Sancho ()
Additional contact information
Annalaura Mastrangelo: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Iñaki Robles-Vera: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Diego Mañanes: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Miguel Galán: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Marcos Femenía-Muiña: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Ana Redondo-Urzainqui: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Rafael Barrero-Rodríguez: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Eleftheria Papaioannou: Spanish National Research Council–Universidad Autónoma de Madrid
Joaquín Amores-Iniesta: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Ana Devesa: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Manuel Lobo-González: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Alba Carreras: University of Gothenburg
Katharina R. Beck: University of Gothenburg
Sophie Ivarsson: University of Gothenburg
Anders Gummesson: University of Gothenburg
Georgios Georgiopoulos: National and Kapodistrian University of Athens Medical School
Manuel Rodrigo-Tapias: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Sarai Martínez-Cano: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Ivan Fernández-López: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Vanessa Nuñez: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Alessia Ferrarini: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Naohiro Inohara: University of Michigan Medical School
Kimon Stamatelopoulos: National and Kapodistrian University of Athens Medical School
Alberto Benguría: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Danay Cibrian: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Francisco Sánchez-Madrid: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Vanesa Alonso-Herranz: Universidad San Pablo-CEU
Ana Dopazo: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Coral Barbas: Universidad San Pablo-CEU
Jesús Vázquez: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Juan Antonio López: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Alicia González-Martín: Spanish National Research Council–Universidad Autónoma de Madrid
Gabriel Nuñez: University of Michigan Medical School
Konstantinos Stellos: Heidelberg University
Göran Bergström: University of Gothenburg
Fredrik Bäckhed: University of Gothenburg
Valentín Fuster: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Borja Ibañez: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
David Sancho: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)

Nature, 2025, vol. 645, issue 8079, 254-261

Abstract: Abstract Atherosclerosis is the main underlying cause of cardiovascular diseases. Its prevention is based on the detection and treatment of traditional cardiovascular risk factors1. However, individuals at risk for early vascular disease often remain unidentified2. Recent research has identified new molecules in the pathophysiology of atherosclerosis3, 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.

Date: 2025
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DOI: 10.1038/s41586-025-09263-w

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