title: Fractalkine neutralization improves cardiac function after myocardial infarction.
abstract: What is the central question of this study? What is the cardioprotective role of fractalkine neutralization in heart failure and what are the mechanisms responsible? What is the main finding and its importance? The concentration of fractalkine is increased in the left ventricle of mice with myocardial infarction, similar to the increases in plasma from heart failure patients. The present study shows a clear beneficial effect of neutralizing fractalkine in a model of myocardial infarction, which results in increased survival. Such an approach may be worthwhile in human patients. Concentrations of the chemokine fractalkine (FKN) are increased in patients with chronic heart failure, and our previous studies show that aged mice lacking the prostaglandin E2 EP4 receptor subtype (EP4-KO) have increased cardiac FKN, with a phenotype of dilated cardiomyopathy. However, how FKN participates in the pathogenesis of heart failure has rarely been studied. We hypothesized that FKN contributes to the pathogenesis of heart failure and that anti-FKN treatment prevents heart failure induced by myocardial infarction (MI) more effectively in EP4-KO mice. Male EP4-KO mice and wild-type littermates underwent sham or MI surgery and were treated with an anti-FKN antibody or control IgG. At 2 weeks post-MI, echocardiography was performed and hearts were excised for determination of infarct size, immunohistochemistry and Western blot of signalling molecules. Given that FKN protein levels in the left ventricle were increased to a similar extent in both strains after MI and that anti-FKN treatment improved survival and cardiac function in both strains, we subsequently used only wild-type mice to examine the mechanisms whereby anti-FKN is cardioprotective. Myocyte cross-sectional area and interstitial collagen fraction were reduced after anti-FKN treatment, as were macrophage migration and gelatinase activity. Activation of ERK1/2 and p38 MAPK were reduced after neutralization of FKN. In vitro, FKN increased fibroblast proliferation. In conclusion, increased FKN contributes to heart failure after MI. This effect is not exacerbated in EP4-KO mice, suggesting that there is no link between FKN and lack of EP4. Overall, inhibition of FKN may be important to preserve cardiac function post-MI.
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, 48202, USA.|Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Gu
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, 48202, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Xu
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, 48202, USA.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, 48202, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Peterson
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, 48202, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Harding
mesh_terms: D000818:Animals; D054428:Chemokine CX3CL1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D004195:Disease Models, Animal; D006333:Heart Failure / Q000503:physiopathology; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D054428:Chemokine CX3CL1