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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

M2 Macrophages are Significantly Enhanced Following FGF-9 Treatment.A-O: Representative photomicrographs demonstrate CD206 positive M2 macrophages 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: Quantitative data suggest that M2 macrophage concentrations are significantly greater in the MI+FGF-9 group relative to sham and MI groups. n = 5 animals/group. Q: Anti-inflammatory IL-10 mRNA expression, evaluated by RT-PCR, was significantly upregulated post-FGF-9 treatment. *p<0.05 vs. sham and #p<0.05 vs. MI.
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pone.0120739.g004: M2 Macrophages are Significantly Enhanced Following FGF-9 Treatment.A-O: Representative photomicrographs demonstrate CD206 positive M2 macrophages 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: Quantitative data suggest that M2 macrophage concentrations are significantly greater in the MI+FGF-9 group relative to sham and MI groups. n = 5 animals/group. Q: Anti-inflammatory IL-10 mRNA expression, evaluated by RT-PCR, was significantly upregulated post-FGF-9 treatment. *p<0.05 vs. sham and #p<0.05 vs. MI.

Mentions: Representative images of heart sections shown in Fig. 4A-O depict CD206 positive M2 macrophages 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). Although not statistically significant, a decrease in M2 macrophage populations was observed in the MI group relative to the sham group (Fig. 4P). Importantly, results showed significantly elevated M2 macrophage concentrations in MI+FGF-9 hearts relative to sham and MI groups, suggesting FGF-9 may play a role in monocyte to M2 macrophage differentiation (p<0.05, Fig. 4P). Furthermore, mRNA expression of IL-10, an anti-inflammatory cytokine produced by alternatively activated M2 macrophages, was significantly upregulated in the MI+FGF-9 group relative to the MI group (p<0.05, Fig. 4Q) [26].


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)

M2 Macrophages are Significantly Enhanced Following FGF-9 Treatment.A-O: Representative photomicrographs demonstrate CD206 positive M2 macrophages 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: Quantitative data suggest that M2 macrophage concentrations are significantly greater in the MI+FGF-9 group relative to sham and MI groups. n = 5 animals/group. Q: Anti-inflammatory IL-10 mRNA expression, evaluated by RT-PCR, was significantly upregulated post-FGF-9 treatment. *p<0.05 vs. sham and #p<0.05 vs. MI.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0120739.g004: M2 Macrophages are Significantly Enhanced Following FGF-9 Treatment.A-O: Representative photomicrographs demonstrate CD206 positive M2 macrophages 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: Quantitative data suggest that M2 macrophage concentrations are significantly greater in the MI+FGF-9 group relative to sham and MI groups. n = 5 animals/group. Q: Anti-inflammatory IL-10 mRNA expression, evaluated by RT-PCR, was significantly upregulated post-FGF-9 treatment. *p<0.05 vs. sham and #p<0.05 vs. MI.
Mentions: Representative images of heart sections shown in Fig. 4A-O depict CD206 positive M2 macrophages 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). Although not statistically significant, a decrease in M2 macrophage populations was observed in the MI group relative to the sham group (Fig. 4P). Importantly, results showed significantly elevated M2 macrophage concentrations in MI+FGF-9 hearts relative to sham and MI groups, suggesting FGF-9 may play a role in monocyte to M2 macrophage differentiation (p<0.05, Fig. 4P). Furthermore, mRNA expression of IL-10, an anti-inflammatory cytokine produced by alternatively activated M2 macrophages, was significantly upregulated in the MI+FGF-9 group relative to the MI group (p<0.05, Fig. 4Q) [26].

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