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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 Blunts Monocyte Infiltration in Infarcted Diabetic Myocardium.A-O: Representative photomicrographs illustrate CD14 positive monocytes in red (A, F, and K), cardiac myocytes in green (B, G, and L), total nuclei in blue (C, H, and M), merged images (D, I, and N), and enhanced merged images (E, J, and O) for all control and experimental groups. White arrows are used to show the areas enhanced in D, I, and N. Scale bar = 75μm. P: Histogram of quantitative monocyte infiltration data 2 weeks post-MI. n = 5 animals/group. *p<0.05 vs. sham and #p<0.05 vs. MI.
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pone.0120739.g002: FGF-9 Blunts Monocyte Infiltration in Infarcted Diabetic Myocardium.A-O: Representative photomicrographs illustrate CD14 positive monocytes in red (A, F, and K), cardiac myocytes in green (B, G, and L), total nuclei in blue (C, H, and M), merged images (D, I, and N), and enhanced merged images (E, J, and O) for all control and experimental groups. White arrows are used to show the areas enhanced in D, I, and N. Scale bar = 75μm. P: Histogram of quantitative monocyte infiltration data 2 weeks post-MI. n = 5 animals/group. *p<0.05 vs. sham and #p<0.05 vs. MI.

Mentions: To extrapolate mechanisms by which FGF-9 protects endogenous myocardial architecture post-MI, inflammatory cells, specifically monocytes, were quantified. Fig. 2A-O contains representative photomicrographs of heart sections stained with CD14, a marker for monocytes, in red (A, F, and K), sarcomeric α-actin for cardiac myocytes in green (B, G, and L), DAPI for nuclei in blue (C, H, and M), merged images (D, I, and N), and enhanced merged images (E, J, and O). Quantitative analysis suggests a significant upregulation of infiltrated monocytes following MI relative to the sham group (p<0.05, Fig. 2P). Conversely, monocyte infiltration was significantly reduced upon FGF-9 treatment compared to the MI group (p<0.05, Fig. 2P).


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 Blunts Monocyte Infiltration in Infarcted Diabetic Myocardium.A-O: Representative photomicrographs illustrate CD14 positive monocytes in red (A, F, and K), cardiac myocytes in green (B, G, and L), total nuclei in blue (C, H, and M), merged images (D, I, and N), and enhanced merged images (E, J, and O) for all control and experimental groups. White arrows are used to show the areas enhanced in D, I, and N. Scale bar = 75μm. P: Histogram of quantitative monocyte infiltration data 2 weeks post-MI. n = 5 animals/group. *p<0.05 vs. sham and #p<0.05 vs. MI.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359124&req=5

pone.0120739.g002: FGF-9 Blunts Monocyte Infiltration in Infarcted Diabetic Myocardium.A-O: Representative photomicrographs illustrate CD14 positive monocytes in red (A, F, and K), cardiac myocytes in green (B, G, and L), total nuclei in blue (C, H, and M), merged images (D, I, and N), and enhanced merged images (E, J, and O) for all control and experimental groups. White arrows are used to show the areas enhanced in D, I, and N. Scale bar = 75μm. P: Histogram of quantitative monocyte infiltration data 2 weeks post-MI. n = 5 animals/group. *p<0.05 vs. sham and #p<0.05 vs. MI.
Mentions: To extrapolate mechanisms by which FGF-9 protects endogenous myocardial architecture post-MI, inflammatory cells, specifically monocytes, were quantified. Fig. 2A-O contains representative photomicrographs of heart sections stained with CD14, a marker for monocytes, in red (A, F, and K), sarcomeric α-actin for cardiac myocytes in green (B, G, and L), DAPI for nuclei in blue (C, H, and M), merged images (D, I, and N), and enhanced merged images (E, J, and O). Quantitative analysis suggests a significant upregulation of infiltrated monocytes following MI relative to the sham group (p<0.05, Fig. 2P). Conversely, monocyte infiltration was significantly reduced upon FGF-9 treatment compared to the MI group (p<0.05, Fig. 2P).

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