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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 Treatment Augments Pro- and Anti-Inflammatory Cytokine Secretion.2 weeks following MI, heart homogenates were used to quantify pro- and anti-inflammatory cytokine secretion via ELISA analysis. Pro-inflammatory cytokine expression, including that of TNF-α, MCP-1, and IL-6, are shown in A, B, and C, respectively whereas anti-inflammatory IL-10 and IL-1RA cytokine expression are depicted in D and E, respectively. n = 5 animals/group. *p<0.05 vs. sham and #p<0.05 vs. MI.
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pone.0120739.g005: FGF-9 Treatment Augments Pro- and Anti-Inflammatory Cytokine Secretion.2 weeks following MI, heart homogenates were used to quantify pro- and anti-inflammatory cytokine secretion via ELISA analysis. Pro-inflammatory cytokine expression, including that of TNF-α, MCP-1, and IL-6, are shown in A, B, and C, respectively whereas anti-inflammatory IL-10 and IL-1RA cytokine expression are depicted in D and E, respectively. n = 5 animals/group. *p<0.05 vs. sham and #p<0.05 vs. MI.

Mentions: Next, we evaluated the effects of FGF-9 treatment on translated pro-inflammatory cytokine expression, including TNF-α, MCP-1, and IL-6. Quantification of TNF-α expression via a TNF-α ELISA indicated significantly escalated TNF-α levels in the MI group relative to sham controls (p<0.05, Fig. 5A). However, treatment with FGF-9 attenuated levels of TNF-α compared to the MI group (p<0.05, Fig. 5A). Results from the MCP-1 ELISA indicated increased levels of MCP-1 in the MI group as compared to the sham group (p<0.05, Fig. 5B). Conversely, the MI+FGF-9 group had significantly decreased MCP-1 expression compared to the MI group (p<0.05, Fig. 5B). Additionally, levels of IL-6 were assessed and quantitative analysis of MI tissues showed up-regulated IL-6 levels compared to sham, whereas the MI+FGF-9 group had significantly down-regulated IL-6 expression relative to expression levels in the MI group (p<0.05, Fig. 5C). Our data collectively suggest that FGF-9 promotes cardioprotection post-MI through mechanisms that contribute to down-regulated pro-inflammatory cytokine expression.


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 Treatment Augments Pro- and Anti-Inflammatory Cytokine Secretion.2 weeks following MI, heart homogenates were used to quantify pro- and anti-inflammatory cytokine secretion via ELISA analysis. Pro-inflammatory cytokine expression, including that of TNF-α, MCP-1, and IL-6, are shown in A, B, and C, respectively whereas anti-inflammatory IL-10 and IL-1RA cytokine expression are depicted in D and E, respectively. 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.g005: FGF-9 Treatment Augments Pro- and Anti-Inflammatory Cytokine Secretion.2 weeks following MI, heart homogenates were used to quantify pro- and anti-inflammatory cytokine secretion via ELISA analysis. Pro-inflammatory cytokine expression, including that of TNF-α, MCP-1, and IL-6, are shown in A, B, and C, respectively whereas anti-inflammatory IL-10 and IL-1RA cytokine expression are depicted in D and E, respectively. n = 5 animals/group. *p<0.05 vs. sham and #p<0.05 vs. MI.
Mentions: Next, we evaluated the effects of FGF-9 treatment on translated pro-inflammatory cytokine expression, including TNF-α, MCP-1, and IL-6. Quantification of TNF-α expression via a TNF-α ELISA indicated significantly escalated TNF-α levels in the MI group relative to sham controls (p<0.05, Fig. 5A). However, treatment with FGF-9 attenuated levels of TNF-α compared to the MI group (p<0.05, Fig. 5A). Results from the MCP-1 ELISA indicated increased levels of MCP-1 in the MI group as compared to the sham group (p<0.05, Fig. 5B). Conversely, the MI+FGF-9 group had significantly decreased MCP-1 expression compared to the MI group (p<0.05, Fig. 5B). Additionally, levels of IL-6 were assessed and quantitative analysis of MI tissues showed up-regulated IL-6 levels compared to sham, whereas the MI+FGF-9 group had significantly down-regulated IL-6 expression relative to expression levels in the MI group (p<0.05, Fig. 5C). Our data collectively suggest that FGF-9 promotes cardioprotection post-MI through mechanisms that contribute to down-regulated pro-inflammatory cytokine expression.

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