Opposing actions of fibroblast and cardiomyocyte smad3 signaling in the infarcted myocardium

Ping Kong, Arti V. Shinde, Ya Su, Ilaria Russo, Bijun Chen, Amit Saxena, Simon Conway, Jonathan M. Graff, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: Transforming growth factor-βs regulate a wide range of cellular responses by activating Smad-dependent and Smad-independent cascades. In the infarcted heart, Smad3 signaling is activated in both cardiomyocytes and interstitial cells. We hypothesized that cell-specific actions of Smad3 regulate repair and remodeling in the infarcted myocardium. Methods: To dissect cell-specific Smad3 actions in myocardial infarction, we generated mice with Smad3 loss in activated fibroblasts or cardiomyocytes. Cardiac function was assessed after reperfused or nonreperfused infarction using echocardiography. The effects of cell-specific Smad3 loss on the infarcted heart were studied using histological studies, assessment of protein, and gene expression levels. In vitro, we studied Smad-dependent and Smad-independent actions in isolated cardiac fibroblasts. Results: Mice with fibroblast-specific Smad3 loss had accentuated adverse remodeling after reperfused infarction and exhibited an increased incidence of late rupture after nonreperfused infarction. The consequences of fibroblast-specific Smad3 loss were not a result of effects on acute infarct size but were associated with unrestrained fibroblast proliferation, impaired scar remodeling, reduced fibroblast-derived collagen synthesis, and perturbed alignment of myofibroblast arrays in the infarct. Polarized light microscopy in Sirius red-stained sections demonstrated that the changes in fibroblast morphology were associated with perturbed organization of the collagenous matrix in the infarcted area. In contrast,-smooth muscle actin expression by infarct myofibroblasts was not affected by Smad3 loss. Smad3 critically regulated fibroblast function, activating integrin-mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX-2) expression. Smad3 loss in cardiomyocytes attenuated remodeling and dysfunction after infarction. Cardiomyocyte-specific Smad3 loss did not affect acute infarct size but was associated with attenuated cardiomyocyte apoptosis in the remodeling myocardium, accompanied by decreased myocardial NOX-2 levels, reduced nitrosative stress, and lower matrix metalloproteinase-2 expression. Conclusions: In healing myocardial infarction, myofibroblast-and cardiomyocyte-specific activation of Smad3 has contrasting functional outcomes that may involve activation of an integrin/reactive oxygen axis.

Original languageEnglish (US)
Pages (from-to)707-724
Number of pages18
JournalCirculation
Volume137
Issue number7
DOIs
StatePublished - Feb 13 2018

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Cardiac Myocytes
Myocardium
Fibroblasts
Infarction
Myofibroblasts
Integrins
Myocardial Infarction
Polarization Microscopy
NADPH Oxidase
Matrix Metalloproteinase 2
Transforming Growth Factors
NADP
Cicatrix
Smooth Muscle
Echocardiography
Actins
Rupture
Oxidoreductases
Collagen
Apoptosis

Keywords

  • Cardiomyocyte
  • Fibroblast
  • Heart failure
  • Remodeling
  • Smad

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Kong, P., Shinde, A. V., Su, Y., Russo, I., Chen, B., Saxena, A., ... Frangogiannis, N. G. (2018). Opposing actions of fibroblast and cardiomyocyte smad3 signaling in the infarcted myocardium. Circulation, 137(7), 707-724. https://doi.org/10.1161/CIRCULATIONAHA.117.029622

Opposing actions of fibroblast and cardiomyocyte smad3 signaling in the infarcted myocardium. / Kong, Ping; Shinde, Arti V.; Su, Ya; Russo, Ilaria; Chen, Bijun; Saxena, Amit; Conway, Simon; Graff, Jonathan M.; Frangogiannis, Nikolaos G.

In: Circulation, Vol. 137, No. 7, 13.02.2018, p. 707-724.

Research output: Contribution to journalArticle

Kong, P, Shinde, AV, Su, Y, Russo, I, Chen, B, Saxena, A, Conway, S, Graff, JM & Frangogiannis, NG 2018, 'Opposing actions of fibroblast and cardiomyocyte smad3 signaling in the infarcted myocardium', Circulation, vol. 137, no. 7, pp. 707-724. https://doi.org/10.1161/CIRCULATIONAHA.117.029622
Kong, Ping ; Shinde, Arti V. ; Su, Ya ; Russo, Ilaria ; Chen, Bijun ; Saxena, Amit ; Conway, Simon ; Graff, Jonathan M. ; Frangogiannis, Nikolaos G. / Opposing actions of fibroblast and cardiomyocyte smad3 signaling in the infarcted myocardium. In: Circulation. 2018 ; Vol. 137, No. 7. pp. 707-724.
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AU - Shinde, Arti V.

AU - Su, Ya

AU - Russo, Ilaria

AU - Chen, Bijun

AU - Saxena, Amit

AU - Conway, Simon

AU - Graff, Jonathan M.

AU - Frangogiannis, Nikolaos G.

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N2 - Background: Transforming growth factor-βs regulate a wide range of cellular responses by activating Smad-dependent and Smad-independent cascades. In the infarcted heart, Smad3 signaling is activated in both cardiomyocytes and interstitial cells. We hypothesized that cell-specific actions of Smad3 regulate repair and remodeling in the infarcted myocardium. Methods: To dissect cell-specific Smad3 actions in myocardial infarction, we generated mice with Smad3 loss in activated fibroblasts or cardiomyocytes. Cardiac function was assessed after reperfused or nonreperfused infarction using echocardiography. The effects of cell-specific Smad3 loss on the infarcted heart were studied using histological studies, assessment of protein, and gene expression levels. In vitro, we studied Smad-dependent and Smad-independent actions in isolated cardiac fibroblasts. Results: Mice with fibroblast-specific Smad3 loss had accentuated adverse remodeling after reperfused infarction and exhibited an increased incidence of late rupture after nonreperfused infarction. The consequences of fibroblast-specific Smad3 loss were not a result of effects on acute infarct size but were associated with unrestrained fibroblast proliferation, impaired scar remodeling, reduced fibroblast-derived collagen synthesis, and perturbed alignment of myofibroblast arrays in the infarct. Polarized light microscopy in Sirius red-stained sections demonstrated that the changes in fibroblast morphology were associated with perturbed organization of the collagenous matrix in the infarcted area. In contrast,-smooth muscle actin expression by infarct myofibroblasts was not affected by Smad3 loss. Smad3 critically regulated fibroblast function, activating integrin-mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX-2) expression. Smad3 loss in cardiomyocytes attenuated remodeling and dysfunction after infarction. Cardiomyocyte-specific Smad3 loss did not affect acute infarct size but was associated with attenuated cardiomyocyte apoptosis in the remodeling myocardium, accompanied by decreased myocardial NOX-2 levels, reduced nitrosative stress, and lower matrix metalloproteinase-2 expression. Conclusions: In healing myocardial infarction, myofibroblast-and cardiomyocyte-specific activation of Smad3 has contrasting functional outcomes that may involve activation of an integrin/reactive oxygen axis.

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