Differential effects of Smad2 and Smad3 in regulation of macrophage phenotype and function in the infarcted myocardium

J Mol Cell Cardiol. 2022 Oct:171:1-15. doi: 10.1016/j.yjmcc.2022.06.009. Epub 2022 Jul 1.


TGF-βs regulate macrophage responses, by activating Smad2/3. We have previously demonstrated that macrophage-specific Smad3 stimulates phagocytosis and mediates anti-inflammatory macrophage transition in the infarcted heart. However, the role of macrophage Smad2 signaling in myocardial infarction remains unknown. We studied the role of macrophage-specific Smad2 signaling in healing mouse infarcts, and we explored the basis for the distinct effects of Smad2 and Smad3. In infarct macrophages, Smad3 activation preceded Smad2 activation. In contrast to the effects of Smad3 loss, myeloid cell-specific Smad2 disruption had no effects on mortality, ventricular dysfunction and adverse remodeling, after myocardial infarction. Macrophage Smad2 loss modestly, but transiently increased myofibroblast density in the infarct, but did not affect phagocytic removal of dead cells, macrophage infiltration, collagen deposition, and scar remodeling. In isolated macrophages, TGF-β1, -β2 and -β3, activated both Smad2 and Smad3, whereas BMP6 triggered only Smad3 activation. Smad2 and Smad3 had similar patterns of nuclear translocation in response to TGF-β1. RNA-sequencing showed that Smad3, and not Smad2, was the main mediator of transcriptional effects of TGF-β on macrophages. Smad3 loss resulted in differential expression of genes associated with RAR/RXR signaling, cholesterol biosynthesis and lipid metabolism. In both isolated bone marrow-derived macrophages and in infarct macrophages, Smad3 mediated synthesis of Nr1d2 and Rara, two genes encoding nuclear receptors, that may be involved in regulation of their phagocytic and anti-inflammatory properties. In conclusion, the in vivo and in vitro effects of TGF-β on macrophage function involve Smad3, and not Smad2.

Keywords: Macrophage; Myocardial infarction; Remodeling; Smad; TGF-β.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cholesterol
  • Collagen / metabolism
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Myocardial Infarction* / metabolism
  • Myocardium / metabolism
  • Phenotype
  • RNA
  • Smad2 Protein* / metabolism
  • Smad3 Protein* / metabolism
  • Transforming Growth Factor beta / metabolism


  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • RNA
  • Collagen
  • Cholesterol