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A Regulatory Role for SDF‐1/CXCR4 Axis In Promoting TNF‐mediated Cardiac Damage Associated With Alcoholic Cardiomyopath
Author(s) -
Little Janay,
Abad Adam,
Peeran Ahmad,
Haddad George,
Tarzami Sima
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb647
Subject(s) - tumor necrosis factor alpha , alcoholic cardiomyopathy , medicine , downregulation and upregulation , endocrinology , stromal cell , cardiomyopathy , heart failure , vascular endothelial growth factor , apoptosis , cancer research , biology , vegf receptors , biochemistry , gene
Alcoholic cardiomyopathy is a form of heart disease caused by alcohol abuse. Tumor necrosis factor alpha (TNF‐α) plays a role in cardiomyopathy, and can lead to cardiomyocyte apoptosis. Our preliminary data suggests that stromal cell‐derived factor 1 (SDF‐1) stimulates TNF‐α mRNA and protein secretion in cardiomyocytes. Since cardiac expression of SDF‐1 is enhanced in inflammatory cardiomyopathy, we have suggested a regulatory role for SDF‐1/CXCR4 axis in promoting TNF‐α mediated cardiac damage associated with cardiomyopathy. HYPOTHESIS Our central hypothesis is that increased levels of SDF‐1 correlate directly with production of TNF‐α and the severity of pathological changes observed in the setting of alcoholic cardiomyopathy. Vascular endothelial growth factor (VEGF) is linked to vasculogenesis, which is seen in healthy hearts. The decrease in quantity of VEGF has been seen as a contributor to damage of heart tissues along with the increase in SDF‐1 and TNF‐α; studies have presented this to be true, but has yet to be shown or seen in alcoholic hearts. METHODS Littermate adult rats were put on a 3‐months isocaloric Lieber‐Decarli liquid diet with high alcohol (HA: 100mM) levels. Hearts were taken out and concentrations of TNF‐α, SDF‐1, and VEGF were analyzed in protein lysates that were prepared from those hearts. TNF‐α, SDF‐1, and VEGF protein expression was quantified using ELISA assay. To evaluate whether SDF‐1 upregulation mediated TNF‐α expression and subsequent cell death, adult rat cardiomyocytes were freshly isolated and treated with SDF‐1 at different concentrations and apoptosis was assessed using TUNEL at 24hrs post treatment. RESULTS Our data suggests that high alcohol consumption is associated with reduced cardiac contractile function. Moreover, in the setting of alcoholic cardiomyopathy, our preliminary results suggests that SDF‐1 can stimulate production of TNF‐α and subsequent apoptosis possibly contributing to the observed pathophysiology. The ELISA reported that the amount of TNF‐α and SDF‐1 increased in the alcoholic tissues compared to the controls; however, there is a trend toward VEGF downregulation in the alcoholic tissues compared to the controls which can further exacerbate the severity of damage. Treatment of isolated adult rat cardiac myocyte with SDF‐1 at higher concentrations (>30nM) upregualted TNF‐α protein expression and induced subsequent apoptosis. CONCLUSION Our data suggests a SDF‐1/CXCR4 network regulates TNF‐α production in cardiomyocytes leading to pathological changes observed in alcoholic cardiomyopathy e.g. myocyte apoptosis. Support or Funding Information Research report in this publication was supported by the American Physiological Society under grant number NHLBI; R25 HL115473‐01