Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis.

Publication

Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis.

Journal Paper/Review - Feb 19, 2024

Pérez Shibayama Christian Ivan, Gil Cruz Cristina, Cadosch Nadine, Lütge Mechthild, Cheng Hung-Wei, De Martin Angelina, Frischmann Kira, Joachimbauer Anna, Onder Lucas, Papadopoulou Iliana, Papadopoulou Chrysa, Ring Sandra Stephanie, Krebs Philippe, P. Vu Vivian, P. Nägele Matthias, Rossi Valentina A, Parianos Danae, Zsilavecz Valentin W, Cooper Leslie T., Flammer Andreas J, Ruschitzka Frank, Rainer Peter P, Schmidt Dörthe, Ludewig Burkhard

Citation

Pérez Shibayama C, Gil Cruz C, Cadosch N, Lütge M, Cheng H, De Martin A, Frischmann K, Joachimbauer A, Onder L, Papadopoulou I, Papadopoulou C, Ring S, Krebs P, P. Vu V, P. Nägele M, Rossi V, Parianos D, Zsilavecz V, Cooper L, Flammer A, Ruschitzka F, Rainer P, Schmidt D, Ludewig B. Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis. Nat Cardiovasc Res 2024; 3:301-316.

Type

Journal Paper/Review (English)

Journal

Nat Cardiovasc Res 2024; 3

Publication Date

Feb 19, 2024

Issn Electronic

2731-0590

Pages

301-316

Brief description/objective

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.