Fibroblast Growth Factor-9 Enhances M2 Macrophage Differentiation and Attenuates Adverse Cardiac Remodeling in the Infarcted Diabetic Heart

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.

Scarless wound healing: finding the right cells and signals

“…Fibroblast growth factor 9 (Fgf9) also provides a means for modulating the inflammatory environment, for example by promoting monocyte to M2 macrophage differentiation in cardiac ischemic injury (Singla, et al, 2015). Importantly in cutaneous injury, Fgf9 from dermal γδ T cells was shown by Gay et al to facilitate follicle neogenesis.…”

IL-4 as a Repurposed Biological Drug for Myocardial Infarction through Augmentation of Reparative Cardiac Macrophages: Proof-of-Concept Data in Mice

“…This treatment will encourage formation of more solid scar tissue, resolution of acute inflammation, and attenuation of post-MI adverse ventricular remodeling. Previous studies have reported several methods to increase cardiac M2 macrophages, including intramyocardial injection of microparticles loaded with fibroblast growth factor-2 with hepatocyte growth factor 12 , intravenous injection of phosphatidylserine-presenting liposomes 13 , intramyocardial injection of FGF-9 14 , administration of superagonistic CD28-specific monoclonal antibodies 15 , and intramyocardial transplantation of mesenchymal stem cells 16 . However, these are technically challenging and none of them has been established in the clinical arena yet.…”

PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy

“…At day 56, after the final injection, two-dimensional echocardiography was performed under 2% isoflurane (Butler Animal Health Supply) delivered via nose cone to evaluate heart function, as previously described (46). In brief, a 15-6L hockey stick transducer was used to capture M-mode images of left ventricular (LV) internal dimension during diastole (LVIDd) and LV internal dimension during systole (LVIDs).…”

“…TUNEL assay was performed as previously reported (47). Formalin-preserved hearts were embedded in paraffin, cut into 5-m serial sections, and placed on Colorfrost slides as previously described (46). Slides were deparaffinized and rehydrated using xylene, 50% xylene-50% absolute alcohol, and decreasing ethanol solutions.…”

“…Recent data suggest that inflammatory cells, such as monocytes and macrophages, are involved in cardiovascular diseases, such as atherosclerosis and diabetic-induced myocardial infarctions (45,46). Monocytes travel to the site of injury and undergo differentiation into either proinflammatory M1 macrophages or anti-inflammatory M2 macrophages.…”