Abstract 19462: N-terminal Region of Cardiac Myosin Binding Protein-C is Proinflammatory Following Myocardial Infarction
Introduction: Myocardial infarction (MI) promotes inflammation within the heart through the recruitment and activation of innate and adaptive cells of the immune system, contributing to the development of dilated cardiomyopathy (DCM). Cardiac myosin binding protein-C (cMyBP-C), a regulatory protein of the cardiac sarcomere, is highly degraded following MI releasing a predominant N-terminal 40kDa fragment (C0C1f) into the local heart tissue and systemic circulation. However, whether released cMyBP-C promotes proinflammatory cytokine expression and/or autoantibody (AAb) production leading to myocardial inflammation in MI patients has not been studied.
Hypothesis: C0C1f-targeted AAbs are produced in MI patients and that C0C1f causes proinflammatory immune cell activation.
Methods and Results: We performed indirect ELISA using sera from 631 MI patients upon arrival to the emergency department and 139 control individuals to elucidate whether C0C1f is immunogenic leading to AAb production in MI patients. AAbs targeted to C0C1f were identified in 28 MI patients by ELISA, which was confirmed by Western blot analysis. Competitive ELISA demonstrated that these AAbs were specifically targeted to C0C1f. To determine whether C0C1f leads to activation of immune cells, bone marrow derived mouse monocytes were cultured with different N-terminal regions of cMyBP-C for 3, 6, 9, and 24 hrs. After 6 hrs of incubation, recombinant mouse C0C1f produced marked elevation in the inflammatory markers TNFα, proIL1b, IL1b, and IL6 and in the adhesion markers VCAM and ICAM in mouse monocytes. After 24 hrs of incubation with C0C1f, the levels of the anti-inflammatory marker Mrc1 were noticeably reduced in mouse monocytes. Similar results were obtained using human bone marrow-derived monocytes cultured with human C0C1f.
Conclusions: These results implicate the C0C1f fragment of cMyBP-C as proinflammatory leading to activation of innate and adaptive immune responses that may contribute to myocardial inflammation following MI.
Author Disclosures: T.L. Lynch: None. C. Liebetrau: None. L. Pyttel: None. C. Troidl: None. S. Sadayappan: None.
- © 2014 by American Heart Association, Inc.