Clin Res Cardiol (2021) DOI DOI https://doi.org/10.1007/s00392-021-01843-w

Post-Myocardial Infarction Heart Failure induces type H vasculature loss on the Bone Vascular Niche via IL1B and MYC

G. Luxán1, J. Hoffmann2, W. Abplanalp3, S.-F. Glaser1, T. Rasper1, A. Fischer1, M. Muhly-Reinholz1, D. John1, B. Aßmus4, A. M. Zeiher2, S. Dimmeler1

1Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration, Goethe Universität Frankfurt am Main, Frankfurt am Main; 2Med. Klinik III - Kardiologie Zentrum der Inneren Medizin, Universitätsklinikum Frankfurt, Frankfurt am Main; 3Institute of Cardiovascular Regeneration and Department of Cardiology, Goethe Universität Frankfurt am Main, Frankfurt am Main; 4Medizinische Klinik I - Kardiologie und Angiologie, Universitätsklinikum Gießen und Marburg GmbH, Gießen;

Endothelial cells provide protection and signals necessary to control stem cell quiescence and renewal in the bone. Specifically, type H capillaries, characterized by the high expression of Endomucin and CD31, constitute the endothelial niche supporting a microenvironment of osteoprogenitors and long-term hematopoietic stem cells. Type H capillary numbers decline with age, and this decline is associated with bone dysregulation, accumulation of hematopoietic stem cells with reduced functionality. Nonetheless the effect on bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the vascular bone cell composition. We demonstrate an age-independent loss of type H bone endothelium in heart failure after myocardial infarction in both mice and in humans accompanied by a myeloid progenitor expansion. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure especially in the type H endothelium. Mechanistically, we have observed that IL1B induces the expression of MYC on endothelial cells and that the overexpression of MYC on the vasculature is sufficient to induce the loss of type H vasculature in the bone (P=0.0041, N=4). Inhibition of NLRP3-dependent IL-1β production partially prevents the post-myocardial infarction loss of type H vasculature in mice (P=0.036, N=6). Taken together these results suggest that IL1B via MYC induces the loss of type H endothelial cells and provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of vascular bone function in ischemic heart disease.

https://dgk.org/kongress_programme/jt2021/aP526.html