Carnosinylation of Cardiac Antigens Attenuates Immunogenic Responses and Improves Function in Failing Hearts

Abstract

ObjectiveTo investigate the effects of carnosine on heart failure and to examine whether this is associated with reduced immunogenicity of oxidatively-generated aldehyde modified proteins. BackgroundHeart failure is associated with the accumulation of lipid derived aldehydes that form immunogenic protein adducts. However, the pathological impact of these aldehydes and aldehyde-modified proteins in heart failure has not been assessed. Histidyl dipeptides, such as carnosine found in the heart, bind to aldehydes, and their protein adducts. However, the effects of carnosine on heart failure or the antigenicity of aldehyde modified proteins have not been studied. MethodsMale, wild type C57BL/6J mice were subjected to either sham or transverse aortic constriction (TAC) surgery. To increase carnosine levels, they were placed on drinking water with or without {beta}-alanine prior to surgery, and for the remainder of the study. Cardiac function was evaluated by echocardiography, and the levels of histidyl dipeptides, immune cell populations, and CD4+ T cell activation were assessed via LC-MS/MS and flow cytometry, respectively. ResultsMyocardial levels of histidyl dipeptides decreased at both 3- and 8-weeks post-TAC. Supplementation with {beta}-alanine increased myocardial histidyl dipeptide levels, attenuated adverse cardiac remodeling, and reduced aldehyde stress. Carnosine formed covalent bond with protein-bound aldehydes in the failing heart, reducing their antigenic potential and decreasing activation of dendritic cells and CD4+ T cells in vitro. {beta}-alanine supplementation decreased the population of CD11b+CD64-Ly6G+ neutrophils and CD4+ CD44+ effector T cells in the failing heart. ConclusionsIncreasing myocardial carnosine levels reduces aldehyde stress, dampens maladaptive immune responses, and preserves cardiac function during heart failure. HIGHLIGHTSO_LILevels of endogenous dipeptide carnosine are depleted in failing hearts, while supplementation of the carnosine precurson {beta}-alanine increases myocardial carnosine and preserves cardiac function during heart failure. C_LIO_LIHeart failure is associated with increased activation and infiltration of CD4+ T cells and generation of aldehyde modified protein adducts in failing hearts. C_LIO_LIThe free aldehyde moiety of aldehyde modified protein adducts activates CD4+ T cells through dendritic cell presentation and capping this moiety with carnosine diminishes their antigencity. C_LIO_LIIncreasing myocardial carnosine levels diminishes aldehyde stress and activation of CD4+ T cells during heart failure. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/671840v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@28fc7corg.highwire.dtl.DTLVardef@d851ccorg.highwire.dtl.DTLVardef@1e24a5dorg.highwire.dtl.DTLVardef@18023b6_HPS_FORMAT_FIGEXP M_FIG C_FIG