Microbial Imidazole Propionate: A key mediator in promoting fibrotic cellular response and the progression of heart failure.

Vanasa Nageswaran (Berlin)1, P. Ramezani Rad (Berlin)1, A. Victor (Berlin)1, J. Steinfeldt (Berlin)1, U. Landmesser (Berlin)1, A. Haghikia (Berlin)1

1Charité - Universitätsmedizin Berlin CC 11: Med. Klinik für Kardiologie Berlin, Deutschland


Background and aims:

Alterations of gut microbiota compositions and its metabolites have been increasingly acknowledged to contribute to the risk of cardiovascular diseases (CVDs), including coronary artery disease and heart failure (HF). Imidazole propionate (ImP) is a microbially produced metabolite from the histidine metabolism that has been linked to insulin resistance and type 2 diabetes. However, its role in the development of HF still remains unknown. Here, we investigated the relation between ImP blood levels and HF severity in a clinical cohort as well as its impact on cardiac fibrosis and HF development in vitro and in vivo.

Methods and results:

Plasma ImP levels were examined in a cohort of patients (n=831) diagnosed with cardiac dysfunction and clinical symptoms of HF based on the New York Heart Association (NYHA) classification. Our results showed significantly higher levels of ImP in patients with reduced left ventricular ejection fraction (LVEF) and more severe clinical symptoms of HF from stage 3/4. In experimental settings adult C57BL/6J mice (n=8) were treated with either ImP or the vehicle via drinking water for 8 weeks. Interestingly, the echocardiography results demonstrated significantly reduced LVEF and decreased stroke volume in the ImP animals as compared to the control group. Furthermore, a BrdU cell proliferation assay and Western blotting of primary human cardiac fibroblasts (HCFs) were assessed to identify the potential pathomechanism. HCFs were stimulated with different concentrations of ImP (25, 50, 100, 200 and 500 nM) for 24 hrs. Pro-fibrotic phenotype was observed as evidenced by a dose-dependent increase in cell proliferation of HCFs. This phenotype was efficiently abolished when co-treated with an anti-fibrotic agent, pirfenidone (PFD). In addition, stimulation with 100 nM ImP resulted in increased expression of pro-fibrotic markers, collagen type I alpha 1 (COL1A1) and α-smooth muscle actin (αSMA), in vitro.


Our findings reveal a novel mechanism that associates the microbially produced histidine-derived metabolite ImP to increased proliferation of cardiac fibroblast and the development of HF, suggesting to target ImP production as a potential strategy to prevent cardiac remodeling and HF.

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