Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Perez-Shibayama, C; Gil-Cruz, C; Cadosch, N; Lütge, M; Cheng, HW; De Martin, A; Frischmann, K; Joachimbauer, A; Onder, L; Papadopoulou, I; Papadopoulou, C; Ring, SD; Krebs, P; Vu, VP; Nägele, MP; Rossi, VA; Parianos, D; Zsilavecz, VW; Cooper, LT; Flammer, A; Ruschitzka, F; Rainer, PP; Schmidt, D; Ludewig, B.
Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis
NAT CARDIOVASC RES. 2024;
Doi: 10.1038/s44161-024-00432-0
Web of Science
FullText
FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Rainer Peter
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- Abstract:
- Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4-gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure. Perez-Shibayama et al. report that BMP4 signaling is downregulated in autoimmune myocarditis. Restoring BMP4 levels with antibodies that neutralize the BMP inhibitors gremlin-1 and gremlin-2 can ameliorate cardiac inflammation and improve function in mouse models.