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

• Published in: Journal of molecular and cellular cardiology Vol. 52; no. 1; pp. 154 - 164
• Main Authors: Govindan, Suresh, McElligott, Andrew, Muthusamy, Saminathan, Nair, Nandini, Barefield, David, Martin, Jody L, Gongora, Enrique, Greis, Kenneth D, Luther, Pradeep K, Winegrad, Saul, Henderson, Kyle K, Sadayappan, Sakthivel
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2012
• Subjects: Aged; Aged, 80 and over; Animals; Biomarkers - metabolism; Cardiac biomarker; Cardiac troponin I; Cardiovascular; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Knockout; Middle Aged; Myocardial Infarction - diagnosis; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardium - metabolism; Myocardium - pathology; Myosin binding protein-C; Phosphorylation; Proteolysis; Rats; Rats, Sprague-Dawley; Sandwich ELISA assay; Sarcomeres - metabolism; Time Factors; posterior wall; cTnI; cardiac troponin T; Phosphorylation; Sandwich ELISA assay; cMyBP-C; PW; sodium dodecyl sulfate-polyacrylamide gel electrophoresis; LV; cardiac troponin I; Cardiac biomarker; milliliter; α-tropomyosin; immunoprecipitation; cTnT; left ventricular; MI; cardiac myosin binding protein-C; ml; PBS; myocardial infarction, kDa, kilo Dalton; Myosin binding protein-C; IP; SDS-PAGE; anterior wall; ICM; ischemic cardiomyopathy; nanogram; phosphate buffered saline; AW; enzyme-linked immunosorbent assay; ng; α-TM; ELISA; Cardiac troponin I
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2011.09.011

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.