Cardiac myosin binding protein-C is a potential diagnostic biomarker for myocardial infarction

Abstract

Cardiac myosin binding protein-C (cMyBP-C) is a thick filament assembly protein that stabilizes sarcomeric structure and regulates cardiac function; however, the profile of cMyBP-C degradation after myocardial infarction (MI) is unknown. We hypothesized that cMyBP-C is sensitive to proteolysis and is specifically increased in the bloodstream post-MI in rats and humans. Under these circumstances, elevated levels of degraded cMyBP-C could be used as a diagnostic tool to confirm MI. To test this hypothesis, we first established that cMyBP-C dephosphorylation is directly associated with increased degradation of this myofilament protein, leading to its release in vitro. Using neonatal rat ventricular cardiomyocytes in vitro, we were able to correlate the induction of hypoxic stress with increased cMyBP-C dephosphorylation, degradation, and the specific release of N′-fragments. Next, to define the proteolytic pattern of cMyBP-C post-MI, the left anterior descending coronary artery was ligated in adult male rats. Degradation of cMyBP-C was confirmed by a reduction in total cMyBP-C and the presence of degradation products in the infarct tissue. Phosphorylation levels of cMyBP-C were greatly reduced in ischemic areas of the MI heart compared to non-ischemic regions and sham control hearts. Post-MI plasma samples from these rats, as well as humans, were assayed for cMyBP-C and its fragments by sandwich ELISA and immunoprecipitation analyses. Results showed significantly elevated levels of cMyBP-C in the plasma of all post-MI samples. Overall, this study suggests that cMyBP-C is an easily releasable myofilament protein that is dephosphorylated, degraded and released into the circulation post-MI. The presence of elevated levels of cMyBP-C in the blood provides a promising novel biomarker able to accurately rule in MI, thus aiding in the further assessment of ischemic heart disease.

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

“…Immunoblots of LV tissue lysates were performed and analyzed as described (17,19) with antibodies against SERCA-2a (1:2,000; Thermo Fisher, Waltham, MA), phospholamban (PLB, 1:2,000; Millipore, Billerica, MA), phospho-PLB Ser16 (p-PLB, 1:2,000, Millipore), cardiac troponin I (cTnI) (1:2,000; Cell Signaling, Beverly, MA), phospho-TnI Ser23/24 (1:1,000, Cell Signaling), cMyBP-C (1:5,000) (15), and phospho-cMyBP-C Ser-273, Ser-282, and Ser-302 (1:5,000) (15).…”

Automatizáltan mérhető biomarkerek az akut myocardialis infarctus diagnosztikájában

“…Ígéretes korai markernek tűnik az ischaemiamodifi kált albumin, a hősokkfehérje-27, a katepszin-K, a C1q-kötő adiponectin, a sejtmentes keringő DNS, a májsejt-növekedési faktor, a glikogén foszforiláz BB izoenzim és a növekedést elkülönítő faktor 15 [31,32,33,34,35,36,37,38,39]. A tanulmányok szerint az újonnan vizsgált necrosismarkerek (szívmio-zinkötő fehérje C és sarcoplasmás reticulum Ca 2+ -ATPáz) sokkal szívfajlagosabbak, mint a jelenleg használatosak [40,41,42]. A biomarkerek mellett olyan új képalkotó eljárások is segítik az AMI diagnózisát, mint a szív mág-neses rezonanciás képalkotás (cMRI) és az optikai koherens tomográfi a (OCT) [43,44].…”

Introducing a series of topical special issues of the Journal of Muscle Research and Cell Motility

“…The potential mis-regulation of MyBP-C-linked kinase signalling in heart disease is likely an underestimated factor, as discussed here (Bardswell et al 2012;Knöll 2012;Kuster et al 2012). While N-terminal fragments due to premature stop-codons do not accumulate detectably in the myocardium of HCM patients, ischaemia-reperfusion injury leads to the proteolytic cleavage of cardiac MyBP-C and the liberation of full-length protein and at least two proteolytic fragments (Jacquet et al 2009;Govindan et al 2012a) that show, in agreement with other studies on N-terminal fragments, tight localisation to the A-band (Govindan et al 2012b). This suggests that such proteolytic MyBP-C fragments might exert ectopic effects on myosin regulation that could contribute to contractile failure in the reperfused heart.…”