TY - JOUR
T1 - Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis
AU - Perez-Shibayama, Christian
AU - Gil-Cruz, Cristina
AU - Cadosch, Nadine
AU - Lütge, Mechthild
AU - Cheng, Hung Wei
AU - De Martin, Angelina
AU - Frischmann, Kira
AU - Joachimbauer, Anna
AU - Onder, Lucas
AU - Papadopoulou, Iliana
AU - Papadopoulou, Chrysa
AU - Ring, Sandra
AU - Krebs, Philippe
AU - Vu, Vivian P.
AU - Nägele, Matthias P.
AU - Rossi, Valentina A.
AU - Parianos, Danaë
AU - Zsilavecz, Valentin W.
AU - Cooper, Leslie T.
AU - Flammer, Andreas
AU - Ruschitzka, Frank
AU - Rainer, Peter P.
AU - Schmidt, Dörthe
AU - Ludewig, Burkhard
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/3
Y1 - 2024/3
N2 - 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.
AB - 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.
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U2 - 10.1038/s44161-024-00432-0
DO - 10.1038/s44161-024-00432-0
M3 - Article
AN - SCOPUS:85185260716
SN - 2731-0590
VL - 3
SP - 301
EP - 316
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
IS - 3
ER -