BMP antagonist gremlin 2 limits inflammation after myocardial infarction

Lehanna N. Sanders, John A. Schoenhard, Mohamed A. Saleh, Amrita Mukherjee, Sergey Ryzhov, William G. McMaster, Kristof Nolan, Richard J. Gumina, Thomas B. Thompson, Mark A. Magnuson, David G. Harrison, Antonis K. Hatzopoulos

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Rationale: 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. Objective: To investigate the role of Grem2 during cardiac repair and assess its potential to improve ventricular function after injury. Methods and Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)434-449
Number of pages16
JournalCirculation Research
Volume119
Issue number3
DOIs
StatePublished - Jul 22 2016

Fingerprint

Bone Morphogenetic Proteins
Myocardial Infarction
Inflammation
Cardiac Myocytes
Bone Morphogenetic Protein 2
Ventricular Function
Wounds and Injuries
Cell Adhesion
Proteins
Leukocytes
Endothelial Cells
Phenotype

Keywords

  • Grem2 protein, mouse
  • bone morphogenetic protein 2
  • endothelial cells
  • inflammation
  • myocardial infarction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Sanders, L. N., Schoenhard, J. A., Saleh, M. A., Mukherjee, A., Ryzhov, S., McMaster, W. G., ... Hatzopoulos, A. K. (2016). BMP antagonist gremlin 2 limits inflammation after myocardial infarction. Circulation Research, 119(3), 434-449. https://doi.org/10.1161/CIRCRESAHA.116.308700

BMP antagonist gremlin 2 limits inflammation after myocardial infarction. / Sanders, Lehanna N.; Schoenhard, John A.; Saleh, Mohamed A.; Mukherjee, Amrita; Ryzhov, Sergey; McMaster, William G.; Nolan, Kristof; Gumina, Richard J.; Thompson, Thomas B.; Magnuson, Mark A.; Harrison, David G.; Hatzopoulos, Antonis K.

In: Circulation Research, Vol. 119, No. 3, 22.07.2016, p. 434-449.

Research output: Contribution to journalArticle

Sanders, LN, Schoenhard, JA, Saleh, MA, Mukherjee, A, Ryzhov, S, McMaster, WG, Nolan, K, Gumina, RJ, Thompson, TB, Magnuson, MA, Harrison, DG & Hatzopoulos, AK 2016, 'BMP antagonist gremlin 2 limits inflammation after myocardial infarction', Circulation Research, vol. 119, no. 3, pp. 434-449. https://doi.org/10.1161/CIRCRESAHA.116.308700
Sanders LN, Schoenhard JA, Saleh MA, Mukherjee A, Ryzhov S, McMaster WG et al. BMP antagonist gremlin 2 limits inflammation after myocardial infarction. Circulation Research. 2016 Jul 22;119(3):434-449. https://doi.org/10.1161/CIRCRESAHA.116.308700
Sanders, Lehanna N. ; Schoenhard, John A. ; Saleh, Mohamed A. ; Mukherjee, Amrita ; Ryzhov, Sergey ; McMaster, William G. ; Nolan, Kristof ; Gumina, Richard J. ; Thompson, Thomas B. ; Magnuson, Mark A. ; Harrison, David G. ; Hatzopoulos, Antonis K. / BMP antagonist gremlin 2 limits inflammation after myocardial infarction. In: Circulation Research. 2016 ; Vol. 119, No. 3. pp. 434-449.
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