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Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction.

Schellings MW, Vanhoutte D, Swinnen M, Cleutjens JP, Debets J, van Leeuwen RE, d'Hooge J, Van de Werf F, Carmeliet P, Pinto YM, Sage EH, Heymans S - J. Exp. Med. (2008)

Bottom Line: The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell-matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM).These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI.The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI.

View Article: PubMed Central - PubMed

Affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, University Hospital Maastricht, 6229 HX Maastricht, The Netherlands.

ABSTRACT
The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell-matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM). This study investigated whether SPARC functions in infarct healing and ECM maturation after myocardial infarction (MI). In comparison with wild-type (WT) mice, animals with a targeted inactivation of SPARC exhibited a fourfold increase in mortality that resulted from an increased incidence of cardiac rupture and failure after MI. SPARC- infarcts had a disorganized granulation tissue and immature collagenous ECM. In contrast, adenoviral overexpression of SPARC in WT mice improved the collagen maturation and prevented cardiac dilatation and dysfunction after MI. In cardiac fibroblasts in vitro, reduction of SPARC by short hairpin RNA attenuated transforming growth factor beta (TGF)-mediated increase of Smad2 phosphorylation, whereas addition of recombinant SPARC increased Smad2 phosphorylation concordant with increased Smad2 phosphorylation in SPARC-treated mice. Importantly, infusion of TGF-beta rescued cardiac rupture in SPARC- mice but did not significantly alter infarct healing in WT mice. These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI. The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI.

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SPARC expression is induced after MI. (A) SPARC protein is increased after MI in mice. Representative Western blots of SPARC in remote and infarcted LV from WT mice at 3, 7, and 14 d after MI (n = 4 per time point; *, P < 0.05). (B–D) SPARC immunofluorescent staining (green) is absent in sham-operated hearts (B) and remote LV (R-LV), gradually increases in the infarct border LV (IB-LV; C), and is strongly up-regulated in the infarcted LV (I-LV) 7 d after MI (C and D). (E–J) SPARC expression (E and H) colocalizes with α–smooth muscle cell (SMC) actin–positive myofibroblasts (F and G) and CD45 immunoreactive leukocytes (I and J) in the infarcted LV of WT infarcted hearts 7 d after MI. The insets in H–J show detailed SPARC and CD45 immunoreactive leukocytes. Error bars represent the mean ± SEM. Bars: (B–D, H, and J) 100 μm; (E–G) 50 μm.
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fig1: SPARC expression is induced after MI. (A) SPARC protein is increased after MI in mice. Representative Western blots of SPARC in remote and infarcted LV from WT mice at 3, 7, and 14 d after MI (n = 4 per time point; *, P < 0.05). (B–D) SPARC immunofluorescent staining (green) is absent in sham-operated hearts (B) and remote LV (R-LV), gradually increases in the infarct border LV (IB-LV; C), and is strongly up-regulated in the infarcted LV (I-LV) 7 d after MI (C and D). (E–J) SPARC expression (E and H) colocalizes with α–smooth muscle cell (SMC) actin–positive myofibroblasts (F and G) and CD45 immunoreactive leukocytes (I and J) in the infarcted LV of WT infarcted hearts 7 d after MI. The insets in H–J show detailed SPARC and CD45 immunoreactive leukocytes. Error bars represent the mean ± SEM. Bars: (B–D, H, and J) 100 μm; (E–G) 50 μm.

Mentions: To assess the expression of SPARC in the cardiac healing process, we examined SPARC protein expression in myocardial tissue of WT mice after MI. Immunoblotting of SPARC in noninfarcted remote left ventricle (LV) only revealed a moderate increase of SPARC protein expression at 3 d after MI (Fig. 1 A). In contrast, and concordant with previous findings (3, 4), SPARC protein levels were strongly increased in the infarcted LV at 7 and 14 d after MI (Fig. 1 A). Immunohistochemistry confirmed that SPARC was low to absent in sham-operated (Fig. 1 B) and in noninfarcted remote LV (Fig. 1 C) but abundantly present in the infarcted LV (Fig. 1, C and D). Double immunohistochemistry revealed that SPARC mainly colocalized with α–smooth muscle actin–positive cells (infiltrating myofibroblast; Fig. 1, E–G) and CD45-immunoreactive leukocytes (Fig. 1, H–J). Thus, SPARC protein showed a localized deposition contemporaneous with the formation of granulation tissue and progressive maturation of the infarct scar.


Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction.

Schellings MW, Vanhoutte D, Swinnen M, Cleutjens JP, Debets J, van Leeuwen RE, d'Hooge J, Van de Werf F, Carmeliet P, Pinto YM, Sage EH, Heymans S - J. Exp. Med. (2008)

SPARC expression is induced after MI. (A) SPARC protein is increased after MI in mice. Representative Western blots of SPARC in remote and infarcted LV from WT mice at 3, 7, and 14 d after MI (n = 4 per time point; *, P < 0.05). (B–D) SPARC immunofluorescent staining (green) is absent in sham-operated hearts (B) and remote LV (R-LV), gradually increases in the infarct border LV (IB-LV; C), and is strongly up-regulated in the infarcted LV (I-LV) 7 d after MI (C and D). (E–J) SPARC expression (E and H) colocalizes with α–smooth muscle cell (SMC) actin–positive myofibroblasts (F and G) and CD45 immunoreactive leukocytes (I and J) in the infarcted LV of WT infarcted hearts 7 d after MI. The insets in H–J show detailed SPARC and CD45 immunoreactive leukocytes. Error bars represent the mean ± SEM. Bars: (B–D, H, and J) 100 μm; (E–G) 50 μm.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2626676&req=5

fig1: SPARC expression is induced after MI. (A) SPARC protein is increased after MI in mice. Representative Western blots of SPARC in remote and infarcted LV from WT mice at 3, 7, and 14 d after MI (n = 4 per time point; *, P < 0.05). (B–D) SPARC immunofluorescent staining (green) is absent in sham-operated hearts (B) and remote LV (R-LV), gradually increases in the infarct border LV (IB-LV; C), and is strongly up-regulated in the infarcted LV (I-LV) 7 d after MI (C and D). (E–J) SPARC expression (E and H) colocalizes with α–smooth muscle cell (SMC) actin–positive myofibroblasts (F and G) and CD45 immunoreactive leukocytes (I and J) in the infarcted LV of WT infarcted hearts 7 d after MI. The insets in H–J show detailed SPARC and CD45 immunoreactive leukocytes. Error bars represent the mean ± SEM. Bars: (B–D, H, and J) 100 μm; (E–G) 50 μm.
Mentions: To assess the expression of SPARC in the cardiac healing process, we examined SPARC protein expression in myocardial tissue of WT mice after MI. Immunoblotting of SPARC in noninfarcted remote left ventricle (LV) only revealed a moderate increase of SPARC protein expression at 3 d after MI (Fig. 1 A). In contrast, and concordant with previous findings (3, 4), SPARC protein levels were strongly increased in the infarcted LV at 7 and 14 d after MI (Fig. 1 A). Immunohistochemistry confirmed that SPARC was low to absent in sham-operated (Fig. 1 B) and in noninfarcted remote LV (Fig. 1 C) but abundantly present in the infarcted LV (Fig. 1, C and D). Double immunohistochemistry revealed that SPARC mainly colocalized with α–smooth muscle actin–positive cells (infiltrating myofibroblast; Fig. 1, E–G) and CD45-immunoreactive leukocytes (Fig. 1, H–J). Thus, SPARC protein showed a localized deposition contemporaneous with the formation of granulation tissue and progressive maturation of the infarct scar.

Bottom Line: The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell-matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM).These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI.The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI.

View Article: PubMed Central - PubMed

Affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, University Hospital Maastricht, 6229 HX Maastricht, The Netherlands.

ABSTRACT
The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell-matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM). This study investigated whether SPARC functions in infarct healing and ECM maturation after myocardial infarction (MI). In comparison with wild-type (WT) mice, animals with a targeted inactivation of SPARC exhibited a fourfold increase in mortality that resulted from an increased incidence of cardiac rupture and failure after MI. SPARC- infarcts had a disorganized granulation tissue and immature collagenous ECM. In contrast, adenoviral overexpression of SPARC in WT mice improved the collagen maturation and prevented cardiac dilatation and dysfunction after MI. In cardiac fibroblasts in vitro, reduction of SPARC by short hairpin RNA attenuated transforming growth factor beta (TGF)-mediated increase of Smad2 phosphorylation, whereas addition of recombinant SPARC increased Smad2 phosphorylation concordant with increased Smad2 phosphorylation in SPARC-treated mice. Importantly, infusion of TGF-beta rescued cardiac rupture in SPARC- mice but did not significantly alter infarct healing in WT mice. These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI. The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI.

Show MeSH
Related in: MedlinePlus