BMP Antagonist Gremlin 2 Limits Inflammation After Myocardial Infarction.
We have recently shown that the bone morphogenetic protein (BMP) antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. Our initial studies discovered that Grem2 is strongly induced in the adult heart after experimental myocardial infarction (MI). However, the function of Grem2 and BMP-signaling inhibitors after cardiac injury is currently unknown.



To investigate the role of Grem2 during cardiac repair and assess its potential to improve ventricular function after injury.



Our data show that Grem2 is transiently induced after MI in peri-infarct area cardiomyocytes during the inflammatory phase of cardiac tissue repair. By engineering loss- (Grem2(-/-)) and gain- (TG(Grem2)) of-Grem2-function mice, we discovered that Grem2 controls the magnitude of the inflammatory response and limits infiltration of inflammatory cells in peri-infarct ventricular tissue, improving cardiac function. Excessive inflammation in Grem2(-/-) mice after MI was because of overactivation of canonical BMP signaling, as proven by the rescue of the inflammatory phenotype through administration of the canonical BMP inhibitor, DMH1. Furthermore, intraperitoneal administration of Grem2 protein in wild-type mice was sufficient to reduce inflammation after MI. Cellular analyses showed that BMP2 acts with TNFα to induce expression of proinflammatory proteins in endothelial cells and promote adhesion of leukocytes, whereas Grem2 specifically inhibits the BMP2 effect.



Our results indicate that Grem2 provides a molecular barrier that controls the magnitude and extent of inflammatory cell infiltration by suppressing canonical BMP signaling, thereby providing a novel mechanism for limiting the adverse effects of excessive inflammation after MI.
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.).
Lehanna N
LN
Sanders
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.).
John A
JA
Schoenhard
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.).
Mohamed A
MA
Saleh
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.).
Amrita
A
Mukherjee
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.).
Sergey
S
Ryzhov
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.).
William G
WG
McMaster
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.).
Kristof
K
Nolan
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.).
Richard J
RJ
Gumina
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.).
Thomas B
TB
Thompson
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.).
Mark A
MA
Magnuson
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.).
David G
DG
Harrison
From the Division of Cardiovascular Medicine, Department of Medicine (L.N.S., J.A.S., A.M., R.J.G., A.K.H.), Department of Cell and Developmental Biology (L.N.S., A.K.H.), Division of Clinical Pharmacology, Department of Medicine (M.A.S., W.G.M., D.G.H.), and Division of General Surgery, Department of Surgery (W.G.M.), Vanderbilt University Medical Center, Nashville, TN; Maine Medical Center Research Institute, Scarborough (S.R.); Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH (K.N., T.B.T.); CentraCare Health, St. Cloud, MN (J.A.S.); Cincinnati Children's Hospital Medical Center, OH (A.M.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); and Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN (M.A.M.). antonis.hatzopoulos@vanderbilt.edu.
Antonis K
AK
Hatzopoulos
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D016207:Cytokines; C583032:DMH1 compound; C490088:Grem2 protein, mouse; D011506:Proteins; D011720:Pyrazoles; D011804:Quinolines
Grem2 protein, mouse; bone morphogenetic protein 2; endothelial cells; inflammation; myocardial infarction