Treatment with bone morphogenetic protein 2 limits infarct size after myocardial infarction in mice

Shock. 2013 Apr;39(4):353-60. doi: 10.1097/SHK.0b013e318289728a.

Abstract

Various strategies have been devised to reduce the clinical consequences of myocardial infarction, including acute medical care, revascularization, stem cell transplantations, and more recently, prevention of cardiomyocyte cell death. Activation of embryonic signaling pathways is a particularly interesting option to complement these strategies and to improve the functional performance and survival rate of cardiomyocytes. Here, we have concentrated on bone morphogenetic protein 2 (BMP-2), which induces ectopic formation of beating cardiomyocytes during development in the mesoderm and protects neonatal cardiomyocytes from ischemia-reperfusion injury. In a mouse model of acute myocardial infarction, an i.v. injection of BMP-2 reduced infarct size in mice when given after left anterior descending artery ligation. Mice treated with BMP-2 are characterized by a reduced rate of apoptotic cardiomyocytes both in the border zone of the infarcts and in the remote myocardium. In vitro, BMP-2 increases the frequency of spontaneously beating neonatal cardiomyocytes and the contractile performance under electrical pacing at 2 Hz, preserves cellular adenosine triphosphate stores, and decreases the rate of apoptosis despite the increased workload. In addition, BMP-2 specifically induced phosphorylation of Smad1/5/8 proteins and protected adult cardiomyocytes from long-lasting hypoxia-induced cellular damage and oxidative stress without activation of the cardiodepressant transforming growth factor-β pathway. Our data suggest that BMP-2 treatment may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by improving the contractility of cardiomyocytes and preventing cardiomyocyte cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Benzamides / pharmacology
  • Bone Morphogenetic Protein 2 / administration & dosage
  • Bone Morphogenetic Protein 2 / pharmacology*
  • Cardiotonic Agents / administration & dosage
  • Cardiotonic Agents / pharmacology*
  • Cell Hypoxia / physiology
  • Dioxoles / pharmacology
  • Echocardiography
  • Injections, Intravenous
  • Mice
  • Myocardial Contraction / drug effects
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / pathology
  • Myocytes, Cardiac / pathology
  • Oxidative Stress / physiology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Recombinant Proteins
  • Smad Proteins / metabolism

Substances

  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • Benzamides
  • Bone Morphogenetic Protein 2
  • Cardiotonic Agents
  • Dioxoles
  • Protein Kinase Inhibitors
  • Recombinant Proteins
  • Smad Proteins