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

BACKGROUND

Heart failure is associated with the accumulation of reactive lipid peroxidation-derived aldehydes, such as acrolein, which form immunogenic protein adducts in the heart. Histidyl dipeptides, including carnosine (β-alanine-histidine), can covalently sequester these aldehydes. We tested whether increasing myocardial carnosine through β-alanine supplementation reduces aldehyde stress, limits the immunogenicity of aldehyde-modified proteins, and improves cardiac function during pressure overload-induced heart failure.

METHODS

Male, wild-type C57BL/6J mice underwent sham or transverse aortic constriction (TAC) surgery. β-alanine was administered in drinking water either before TAC or beginning 4 weeks after TAC and continued for the remainder of the study. Cardiac function was evaluated by echocardiography. Myocardial histidyl dipeptides and aldehyde-dipeptide conjugates were quantified by liquid chromatography with tandem mass spectrometry, and immune cell populations and CD4+ T-cell activation were evaluated by flow cytometry.

RESULTS

Myocardial carnosine and anserine levels were decreased at 3 and 8 weeks after TAC. β-alanine administered either before or after TAC increased myocardial histidyl dipeptide levels, attenuated pathological cardiac remodeling and fibrosis, and reduced protein carbonylation in failing hearts. Carnosine binding to aldehyde-modified proteins decreased their antigenic potential. In vitro, this reduced dendritic cell activation and CD4+ T-cell responses. In vivo, β-alanine pretreatment reduced the cardiac infiltration of CD4+ CD44+ effector T cells and CD11b+CD64-Ly6G+ neutrophils.

CONCLUSIONS

Increasing myocardial carnosine mitigates aldehyde stress, reduces the immunogenicity of aldehyde modified proteins and limits maladaptive immune responses, thereby preserving cardiac function during pressure overload. These findings support β-alanine supplementation as a potential therapeutic strategy to attenuate inflammation and improve outcomes in heart failure.