Bone morphogenic protein-4 availability in the cardiac microenvironment controls myocardial inflammation and fibrosis

• 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. Here, single cell transcriptomics analyses of inflamed murine and human myocardial tissues indicated that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in myocarditis patients. Restoration of BMP signaling by antibody-mediated neutralization of the BMP-inhibitors Gremlin-1 and -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 drugable pathway for the treatment of myocardial inflammation limiting the severe sequelae of cardiac fibrosis and heart failure.
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• Cite: 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 S, 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 myocardial inflammation and fibrosis. NCVR 2024. doi: 10.1038/xxx
• Rawdata: E-MTAB-12589 and E-MTAB-12559