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<sup>1</sup>. However, individuals at risk for early vascular disease often remain unidentified<sup>2</sup>. Recent research has identified new molecules in the pathophysiology of atherosclerosis<sup>3</sup>, 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.
Authors
- Diego Mañanes (ORCID: https://orcid.org/0000-0001-7247-6794)
- Rafael Barrero-Rodríguez (ORCID: https://orcid.org/0009-0000-2890-2725)
- Alessia Ferrarini (ORCID: https://orcid.org/0000-0002-4587-6095)
- Francisco Sánchez‐Madrid (ORCID: https://orcid.org/0000-0001-5303-0762)
- J. Amores (ORCID: https://orcid.org/0000-0002-4125-2250)
- Juan Antonio López (ORCID: https://orcid.org/0000-0002-9097-6060)
- Göran M.L. Bergström (ORCID: https://orcid.org/0000-0003-4289-5722)
- Vanessa Núñez (ORCID: https://orcid.org/0000-0002-7473-1514)
- Anders Gummesson (ORCID: https://orcid.org/0000-0003-0024-960X)
- Manuel Lobo-González (ORCID: https://orcid.org/0000-0001-7651-0179)
- Borja Ibáñez (ORCID: https://orcid.org/0000-0002-5036-254X)
- Annalaura Mastrangelo (ORCID: https://orcid.org/0000-0003-2650-0444)
- Georgios Georgiopoulos (ORCID: https://orcid.org/0000-0001-7661-5253)
- Ana Dopazo (ORCID: https://orcid.org/0000-0002-4910-1684)
- Gabriel Núñez (ORCID: https://orcid.org/0000-0002-6529-2695)
- Vanesa Alonso‐Herranz (ORCID: https://orcid.org/0000-0001-8314-789X)
- David Sancho (ORCID: https://orcid.org/0000-0003-2890-3984)
- Fredrik Bäckhed (ORCID: https://orcid.org/0000-0002-4871-8818)
- Ana Devesa (ORCID: https://orcid.org/0000-0001-5981-2546)
- Alberto Benguría (ORCID: https://orcid.org/0000-0002-5536-566X)
- Ana Redondo‐Urzainqui (ORCID: https://orcid.org/0000-0002-5551-4418)
- Sarai Martínez-Cano (ORCID: https://orcid.org/0000-0001-5883-3900)
- Iñaki Robles‐Vera (ORCID: https://orcid.org/0000-0001-6002-9241)
- Alicia González-Martín (ORCID: https://orcid.org/0000-0002-6179-089X)
- Valentı́n Fuster (ORCID: https://orcid.org/0000-0002-9043-9986)
- Katharina R. Beck (ORCID: https://orcid.org/0000-0001-9818-1265)
- Danay Cibrián (ORCID: https://orcid.org/0000-0002-4908-2639)
- Jesús Vázquez (ORCID: https://orcid.org/0000-0003-1461-5092)
- Konstantinos Stellos (ORCID: https://orcid.org/0000-0002-0194-0825)
- Eleftheria Papaioannou (ORCID: https://orcid.org/0000-0003-1770-6600)
- Coral Barbas (ORCID: https://orcid.org/0000-0003-4722-491X)
- Naohiro Inohara (ORCID: https://orcid.org/0000-0002-4215-9349)
- Miguel Á. Galán (ORCID: https://orcid.org/0000-0002-6695-1509)
- Alba Carreras (ORCID: https://orcid.org/0000-0001-8787-8833)
- Kimon Stamatelopoulos
- Ivan Fernández-López
- Manuel Rodrigo-Tapias (ORCID: https://orcid.org/0009-0009-6490-3114)
- Marcos Femenía-Muiña
- Sophie Ivarsson (ORCID: https://orcid.org/0009-0009-4050-9075)
Institutions
- Universidad San Pablo CEU (ES)
- Universidad Complutense de Madrid (ES)
- Helmholtz Association of German Research Centres (DE)
- University of Patras (GR)
- King's College London (GB)
- National and Kapodistrian University of Athens (GR)
- Heidelberg University (DE)
- Cardiovascular Institute of the South (US)
- University of Michigan (US)
- Sahlgrenska University Hospital (SE)
- Novo Nordisk Foundation (DK)
- University Hospital Heidelberg (DE)
- Spanish National Centre for Cardiovascular Research (ES)
- Centro de Investigación en Red en Enfermedades Cardiovasculares (ES)
- Mount Sinai Hospital (US)
- Hospital La Paz Institute for Health Research (ES)
- Inmunotek (Spain) (ES)
- German Centre for Cardiovascular Research (DE)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- Spanish National Centre for Cardiovascular Research (ES)
- Hospital Universitario de La Princesa (ES)
- Osaka International Cancer Institute (JP)
- University Medical Centre Mannheim (DE)
- Universidad Autónoma de Madrid (ES)
- University of Gothenburg (SE)
- Technical University of Denmark (DK)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1038/s41586-025-09263-w
- Citations
- 34
- Primary Topic
- Atherosclerosis and Cardiovascular Diseases
- Type
- article
- Field-Weighted Citation Impact
- 27.11