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Review
. 2014 Aug;8(7-8):569-77.
doi: 10.1002/prca.201400011. Epub 2014 Jul 14.

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

Thomas L Lynch  1 , Sakthivel Sadayappan
Affiliations
Free PMC article
Review

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

Thomas L Lynch et al. Proteomics Clin Appl. 2014 Aug.
Free PMC article

Abstract

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. 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 posttranslational 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.

Keywords: Autoantibodies; Biomarkers; Dilated cardiomyopathy; Myocardial infarction; cMyBP-C.

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Figures

Figure 1
Figure 1
Cardiac morphology and sarcomere structure. (A) Anatomical diagram of the heart showing cardiac vasculature. Inset illustrating myocardial infarction (MI). A leading cause of MI is the rupture of an unstable cholesterol plaque promoting thrombus formation, inflammatory cell infiltration, and occlusion of a coronary artery. The loss of blood supply to distal myocardial tissue inhibits the supply of oxygen and nutrients within the infarct zone and leads to tissue necrosis following prolonged ischemia. The duration of occlusion determines the severity of tissue damage with irreversible necrosis occurring within several hours of the infarct. As such, identifying early markers of MI presence will be vital in the timely diagnosis and treatment of patients in the future. (B) Structure of cMyBP-C in the cardiac sarcomere. The cardiac sarcomere consists of the thick-filament proteins: myosin and titin, as well as the thin-filament proteins: actin, α-tropomyosin, and troponins I, C, and T. cMyBP-C is a sarcomeric protein that participates in stabilizing sarcomere structure and regulating the kinetics of crossbridge cycling by controlling the interaction between actin and myosin filaments.
Figure 2
Figure 2
Mapping of PTMs in cMyBP-C by MS/MS. Elucidating the profile of PTMs that occur within cMyBP-C through proteomics approaches has been and will continue to be essential for determining how these modifications affect the role of cMyBP-C in health and disease. (A) Structurally, cMyBP-C consists of 12 domains of which 8 are immunoglobulin (IgC2) like domains (blue), and three are fibronectin (FN3) domains (purple) . Unique to cMyBP-C is a cardiac-specific C0 domain, a proline–alanine rich linker region (red), an insertion loop within the C5 domain, and a phosphorylation motif at the M-domain (green) . Sites of interaction between cMyBP-C domains and other sarcomeric proteins are shown below. Listed are the PTM sites within mouse cMyBP-C adapted from PhosphoSitePlus® analysis of cMyBP-C PTMs (http://www.phosphosite.org) that have been determined using MS and other techniques. PTM residues are indicated in the text as acetylation (pink), glutathionylation (blue), methylation (brown), phosphorylation (red), and ubiquitination (green). (B) MS/MS represents a highly sensitive analytical tool for identifying the sites and types of PTMs within enriched peptides from a sample of tryptically digested and separated proteins and will be a critical proteomics approach in the future of cMyBP-C PTM discovery. The first MS analysis provides the mass of all peptides in a sample. Specific peptides can then be fragmented to generate ions that undergo another round of MS to determine fragment ion m/z values and peptide sequence by computational analysis . Based upon changes in the mass of modified amino acid residues, MS/MS allows for identification of the type and site of a PTM .
Figure 3
Figure 3
Schematic illustration of cMyBP-C release kinetics in the blood following MI. Cardiac ischemia occurs when the supply of blood to the heart does not appropriately respond to the demand required due to atherosclerosis in the anterior region of the heart and either partial or complete stenosis of a coronary artery by plaque rupture. Symptomatically, this could result in chest pain, which would send patients to the Emergency Department (ED). Prolonged ischemia leads to cellular necrosis, followed by acute MI. Currently, NSTEMI patients are diagnosed on the basis of increased blood levels of cTnI, but this marker of MI only becomes significantly elevated in the blood at 6–12 h after the onset of ischemia, causing critical diagnostic delays before treatment can be initiated. Recently, we detected the presence of cMyBP-C in the plasma of pigs within 30 min of MI , suggesting that cMyBP-C could be a sign of early ischemia in patients with NSTEMI. Interestingly, the C0C1f proteolytic fragment appears to be the first indication of an early ischemic event. Upper panel shows the release kinetics of circulating cMyBP-C and cTnI up to 14 days following ligation of the LAD coronary artery in swine as measured by immunoassay.
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