The neuropeptide cortistatin attenuates experimental autoimmune myocarditis via inhibition of cardiomyogenic T cell-driven inflammatory responses

Abstract

Myocarditis is an inflammatoryandautoimmunecardiovasculardisease thatcauses dilated myocardiopathyandis responsible for high morbidity andmortality worldwide. Cortistatin is a neuropeptide produced by neurons and cells of theimmuneandvascular systems. Besides its action in locomotor activity and sleep, cortistatin inhibits inflammation in different experimental models of autoimmune diseases. However, its role in inflammatory cardiovascular disorders is unexplored. Here, we investigated the therapeutic effects of cortistatin in a well-established preclinical model of experimental autoimmune myocarditis (EAM). EXPERIMENTAL APPROACH We induced EAM by immunization with a fragment of cardiac myosin in susceptiblBalb/cmice.Cortistatin was administered i.p. starting 7, 11 or 15days after EAMinduction.Atday21,we evaluated heart hypertrophy,myocardial injury,cardiac inflammatory infiltration and levels of serum and cardiac inflammatory cytokines, cortistatin and autoantibodies. We determined proliferation and cytokine production by heart draining lymph node cells in response to cardiac myosin restimulation. KEY RESULTS Systemic injection of cortistatin during the effector phase of the disease significantly reduced its prevalence and signs of heart hypertrophy and injury (decreased the levels of brain natriuretic peptide) and impaired myocardial inflammatory cell infiltration. This effect was accompanied by a reduction in self-antigen-specific T-cell responses in lymph nodes and in the levels of cardiomyogenic antibodies and inflammatory cytokines in serum and myocardium. Finally, we found a positive correlation be tween cardiac and systemic cortistatin levels and EAM severity. CONCLUSIONS ANDIMPLICATIONS Cortistatin emerges as a new candidate to treat inflammatory dilated cardiomyopathy