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Fibroblast growth factor-9 enhances M2 macrophage differentiation and attenuates adverse cardiac remodeling in the infarcted diabetic heart.

Singla DK, Singla RD, Abdelli LS, Glass C - PLoS ONE (2015)

Bottom Line: Inflammation has been implicated as a perpetrator of diabetes and its associated complications.MI: 0.85% ± 0.3%; p<0.05) and associated anti-inflammatory cytokines (IL-10 and IL-1RA), reduced adverse remodeling (Mean ± SEM; MI+FGF-9: 11.59% ± 1.2% vs.MI: 33% ± 3.04%; p<0.05), and improved cardiac function (Fractional shortening, Mean ± SEM; MI+FGF-9: 41.51% ± 1.68% vs.

View Article: PubMed Central - PubMed

Affiliation: Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America.

ABSTRACT
Inflammation has been implicated as a perpetrator of diabetes and its associated complications. Monocytes, key mediators of inflammation, differentiate into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages upon infiltration of damaged tissue. However, the inflammatory cell types, which propagate diabetes progression and consequential adverse disorders, remain unclear. The current study was undertaken to assess monocyte infiltration and the role of fibroblast growth factor-9 (FGF-9) on monocyte to macrophage differentiation and cardioprotection in the diabetic infarcted heart. Db/db diabetic mice were assigned to sham, myocardial infarction (MI), and MI+FGF-9 groups. MI was induced by permanent coronary artery ligation and animals were subjected to 2D transthoracic echocardiography two weeks post-surgery. Immunohistochemical and immunoassay results from heart samples collected suggest significantly increased infiltration of monocytes (Mean ± SEM; MI: 2.02% ± 0.23% vs. Sham 0.75% ± 0.07%; p<0.05) and associated pro-inflammatory cytokines (TNF-α, MCP-1, and IL-6), adverse cardiac remodeling (Mean ± SEM; MI: 33% ± 3.04% vs. Sham 2.2% ± 0.33%; p<0.05), and left ventricular dysfunction (Mean ± SEM; MI: 35.4% ± 1.25% vs. Sham 49.19% ± 1.07%; p<0.05) in the MI group. Importantly, treatment of diabetic infarcted myocardium with FGF-9 resulted in significantly decreased monocyte infiltration (Mean ± SEM; MI+FGF-9: 1.39% ± 0.1% vs. MI: 2.02% ± 0.23%; p<0.05), increased M2 macrophage differentiation (Mean ± SEM; MI+FGF-9: 4.82% ± 0.86% vs. MI: 0.85% ± 0.3%; p<0.05) and associated anti-inflammatory cytokines (IL-10 and IL-1RA), reduced adverse remodeling (Mean ± SEM; MI+FGF-9: 11.59% ± 1.2% vs. MI: 33% ± 3.04%; p<0.05), and improved cardiac function (Fractional shortening, Mean ± SEM; MI+FGF-9: 41.51% ± 1.68% vs. MI: 35.4% ± 1.25%; p<0.05). In conclusion, our data suggest FGF-9 possesses novel therapeutic potential in its ability to mediate monocyte to M2 differentiation and confer cardiac protection in the post-MI diabetic heart.

No MeSH data available.


Related in: MedlinePlus

FGF-9 Inhibits Infarct and Fibrosis in the Post-MI Diabetic Myocardium.A-F: Representative images of Masson’s trichrome stained sections are shown depicting infarct (A-C) and interstitial fibrosis (D-F) for control and experimental groups 2 weeks post-MI. Single arrows represent infarcted myocardium. Double arrows represent interstitial fibrosis. G: Histogram of quantitative infarct size analysis suggests a significant decrease in infarct size in the MI+FGF-9 group compared to the MI group. H: Histogram of mean left ventricular cardiac myocyte cross sectional interstitial fibrotic (IF) area (mm2). n = 5–8 animals/group. *p<0.05 vs. sham and #p<0.05 vs. MI.
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pone.0120739.g001: FGF-9 Inhibits Infarct and Fibrosis in the Post-MI Diabetic Myocardium.A-F: Representative images of Masson’s trichrome stained sections are shown depicting infarct (A-C) and interstitial fibrosis (D-F) for control and experimental groups 2 weeks post-MI. Single arrows represent infarcted myocardium. Double arrows represent interstitial fibrosis. G: Histogram of quantitative infarct size analysis suggests a significant decrease in infarct size in the MI+FGF-9 group compared to the MI group. H: Histogram of mean left ventricular cardiac myocyte cross sectional interstitial fibrotic (IF) area (mm2). n = 5–8 animals/group. *p<0.05 vs. sham and #p<0.05 vs. MI.

Mentions: To determine the effects of FGF-9 on infarct size and interstitial fibrosis in the post-MI diabetic heart, Masson’s trichrome staining was performed on heart sections from all study groups. Representative images depicting infarct are shown in Fig. 1A-C and interstitial fibrosis in Fig. 1D-F. Quantitative analysis revealed a significant increase in infarcted myocardium in the MI group relative to the sham-operated group (p<0.05, Fig. 1G). However, when administered FGF-9 post-MI, infarct size was significantly abrogated compared to the MI group (p<0.05, Fig. 1G). Interstitial fibrosis, quantified in the left ventricular myocardium by direct measurement of the blue area using Image J software, was significantly elevated in the MI group relative to the sham group (p<0.05, Fig. 1H). Markedly, the interstitial fibrotic region was significantly reduced following FGF-9 treatment (p<0.05, Fig. 1H). Collectively, our data suggest that treatment with FGF-9 minimizes infarct size as well as blunts fibrosis formation in the post-MI diabetic myocardium.


Fibroblast growth factor-9 enhances M2 macrophage differentiation and attenuates adverse cardiac remodeling in the infarcted diabetic heart.

Singla DK, Singla RD, Abdelli LS, Glass C - PLoS ONE (2015)

FGF-9 Inhibits Infarct and Fibrosis in the Post-MI Diabetic Myocardium.A-F: Representative images of Masson’s trichrome stained sections are shown depicting infarct (A-C) and interstitial fibrosis (D-F) for control and experimental groups 2 weeks post-MI. Single arrows represent infarcted myocardium. Double arrows represent interstitial fibrosis. G: Histogram of quantitative infarct size analysis suggests a significant decrease in infarct size in the MI+FGF-9 group compared to the MI group. H: Histogram of mean left ventricular cardiac myocyte cross sectional interstitial fibrotic (IF) area (mm2). n = 5–8 animals/group. *p<0.05 vs. sham and #p<0.05 vs. MI.
© Copyright Policy
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4359124&req=5

pone.0120739.g001: FGF-9 Inhibits Infarct and Fibrosis in the Post-MI Diabetic Myocardium.A-F: Representative images of Masson’s trichrome stained sections are shown depicting infarct (A-C) and interstitial fibrosis (D-F) for control and experimental groups 2 weeks post-MI. Single arrows represent infarcted myocardium. Double arrows represent interstitial fibrosis. G: Histogram of quantitative infarct size analysis suggests a significant decrease in infarct size in the MI+FGF-9 group compared to the MI group. H: Histogram of mean left ventricular cardiac myocyte cross sectional interstitial fibrotic (IF) area (mm2). n = 5–8 animals/group. *p<0.05 vs. sham and #p<0.05 vs. MI.
Mentions: To determine the effects of FGF-9 on infarct size and interstitial fibrosis in the post-MI diabetic heart, Masson’s trichrome staining was performed on heart sections from all study groups. Representative images depicting infarct are shown in Fig. 1A-C and interstitial fibrosis in Fig. 1D-F. Quantitative analysis revealed a significant increase in infarcted myocardium in the MI group relative to the sham-operated group (p<0.05, Fig. 1G). However, when administered FGF-9 post-MI, infarct size was significantly abrogated compared to the MI group (p<0.05, Fig. 1G). Interstitial fibrosis, quantified in the left ventricular myocardium by direct measurement of the blue area using Image J software, was significantly elevated in the MI group relative to the sham group (p<0.05, Fig. 1H). Markedly, the interstitial fibrotic region was significantly reduced following FGF-9 treatment (p<0.05, Fig. 1H). Collectively, our data suggest that treatment with FGF-9 minimizes infarct size as well as blunts fibrosis formation in the post-MI diabetic myocardium.

Bottom Line: Inflammation has been implicated as a perpetrator of diabetes and its associated complications.MI: 0.85% ± 0.3%; p<0.05) and associated anti-inflammatory cytokines (IL-10 and IL-1RA), reduced adverse remodeling (Mean ± SEM; MI+FGF-9: 11.59% ± 1.2% vs.MI: 33% ± 3.04%; p<0.05), and improved cardiac function (Fractional shortening, Mean ± SEM; MI+FGF-9: 41.51% ± 1.68% vs.

View Article: PubMed Central - PubMed

Affiliation: Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America.

ABSTRACT
Inflammation has been implicated as a perpetrator of diabetes and its associated complications. Monocytes, key mediators of inflammation, differentiate into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages upon infiltration of damaged tissue. However, the inflammatory cell types, which propagate diabetes progression and consequential adverse disorders, remain unclear. The current study was undertaken to assess monocyte infiltration and the role of fibroblast growth factor-9 (FGF-9) on monocyte to macrophage differentiation and cardioprotection in the diabetic infarcted heart. Db/db diabetic mice were assigned to sham, myocardial infarction (MI), and MI+FGF-9 groups. MI was induced by permanent coronary artery ligation and animals were subjected to 2D transthoracic echocardiography two weeks post-surgery. Immunohistochemical and immunoassay results from heart samples collected suggest significantly increased infiltration of monocytes (Mean ± SEM; MI: 2.02% ± 0.23% vs. Sham 0.75% ± 0.07%; p<0.05) and associated pro-inflammatory cytokines (TNF-α, MCP-1, and IL-6), adverse cardiac remodeling (Mean ± SEM; MI: 33% ± 3.04% vs. Sham 2.2% ± 0.33%; p<0.05), and left ventricular dysfunction (Mean ± SEM; MI: 35.4% ± 1.25% vs. Sham 49.19% ± 1.07%; p<0.05) in the MI group. Importantly, treatment of diabetic infarcted myocardium with FGF-9 resulted in significantly decreased monocyte infiltration (Mean ± SEM; MI+FGF-9: 1.39% ± 0.1% vs. MI: 2.02% ± 0.23%; p<0.05), increased M2 macrophage differentiation (Mean ± SEM; MI+FGF-9: 4.82% ± 0.86% vs. MI: 0.85% ± 0.3%; p<0.05) and associated anti-inflammatory cytokines (IL-10 and IL-1RA), reduced adverse remodeling (Mean ± SEM; MI+FGF-9: 11.59% ± 1.2% vs. MI: 33% ± 3.04%; p<0.05), and improved cardiac function (Fractional shortening, Mean ± SEM; MI+FGF-9: 41.51% ± 1.68% vs. MI: 35.4% ± 1.25%; p<0.05). In conclusion, our data suggest FGF-9 possesses novel therapeutic potential in its ability to mediate monocyte to M2 differentiation and confer cardiac protection in the post-MI diabetic heart.

No MeSH data available.


Related in: MedlinePlus