Surviving the infarct: A profile of cardiac myosin binding protein‐C pathogenicity, diagnostic utility, and proteomics in the ischemic myocardium

Abstract

Summary Cardiac myosin binding protein-C (cMyBP-C) is a regulatory protein of the contractile apparatus within the cardiac sarcomere. Ischemic injury to the heart during myocardial infarction (MI) results in the cleavage of cMyBP-C in a phosphorylation-dependent manner and release of an N-terminal fragment (C0C1f) into the circulation. C0C1f has been shown to be pathogenic within cardiac tissue, leading to the development of heart failure (HF). Based on its high levels and early release into the circulation post-MI, C0C1f may serve as a novel biomarker for diagnosing MI more effectively than current clinically used biomarkers. Over time, circulating C0C1f could trigger an autoimmune response leading to myocarditis and progressive cardiac dysfunction. Given the importance of cMyBP-C phosphorylation state in the context of proteolytic cleavage and release into the circulation post-MI, understanding the post-translational modifications (PTMs) of cMyBP-C would help in further elucidating the role of this protein in health and disease. Accordingly, recent studies have implemented the latest proteomics approaches to define the PTMs of cMyBP-C. The use of such proteomics assays may provide accurate quantitation of the levels of cMyBP-C in the circulation following MI, which could, in turn, demonstrate the efficacy of using plasma cMyBP-C as a cardiac-specific early biomarker of MI. In this review, we define the pathogenic and potential immunogenic effects of C0C1f on cardiac function in the post-MI heart. We also discuss the most advanced proteomics approaches now used to determine cMyBP-C PTMs with the aim of validating C0C1f as an early biomarker of MI.

N-terminal fragment of cardiac myosin binding protein-C triggers pro-inflammatory responses in vitro

“…HMBG1) are released passively into the circulation during the early phase of cardiac injury. In contrast, C0C1f is actively released early upon cardiac injury by a calpain-dependent cleavage and can be detected in blood within 30 min of MI [12]. …”

“…The fact that upon MI, C0C1f is released into the circulation prior to cardiac troponins suggests that it may contribute to the initial sterile inflammation [9, 11, 12]. The mechanism of C0C1f release has been studied extensively, showing a correlation between dephosphorylation of cMyBP-C and its µ-calpain-dependent degradation [9].…”

Transformative Impact of Proteomics on Cardiovascular Health and Disease

“…74 Abundant examples in the literature are available, including a special issue on cardiovascular disease that focused on clinical and translational proteomics. [75][76][77][78][79][80][81][82][83][84][85][86][87] One specific example is activity-based protein profiling with proteomic techniques, which is currently being used to annotate the enzymatic proteome and uses chemical probes that target large groups of enzymes that have similar active-site features. 88 Contributing to the posttranscriptional complexity of the proteome are alternative splicing and isoform variants, often with extensive peptide redundancies, that are not easily addressed by standard rules of parsimony when acquired in the context of multidimensional quantitative proteomic studies.…”

The A31P missense mutation in cardiac myosin binding protein C alters protein structure but does not cause haploinsufficiency

“…However, recent epitope mapping experiments revealed that the C-pro polyclonal antibody preferentially reacts with epitopes in C0 and to a lesser extent with other N-terminal domains of cMyBP-C such as the regulatory M-domain [24]. The significance of the strong antigenic nature of C0 is currently unknown, but the N-terminus of cMyBP-C has been identified in the development of immunogenic myocarditis suggesting that it is especially provocative to immune cells [30, 31]. N-terminal proteolytic cleavage products of cMyBP-C that include C0 and that are released during cardiac stress have also been shown to be cardio-toxic [30, 32].…”