An Endogenously Produced Fragment of Cardiac Myosin Binding Protein C is Pathogenic and Can Lead to Heart Failure
Rationale: A stable 40 kD fragment is produced from cardiac myosin binding protein-C (cMyBP-C) when the heart is stressed, using a stimulus such as ischemia reperfusion injury. Elevated levels of the fragment can be detected in both the diseased mouse and human heart but its ability to interfere with normal cardiac function in the intact animal is unexplored.
Objective: To understand the potential pathogenicity of the 40 kD fragment in vivo and to investigate the molecular pathways that could be targeted for potential therapeutic intervention.
Methods and Results: We generated cardiac myocyte-specific transgenic mice (TG) using a Tet-Off inducible system to permit controlled expression of the 40 kD fragment in cardiomyocytes. When 40 kD protein expression is induced by crossing the responder animals with tetracycline transactivator (tTA) mice under conditions where substantial quantities approximating those observed in disease hearts are reached, the double TG (DTG) mice subsequently develop sarcomere dysgenesis, altered cardiac geometry and the heart fails between 3 to 17 weeks of age. The induced DTG mice developed cardiac hypertrophy with myofibrillar disarray and fibrosis, and activation of pathogenic MEK-ERK pathways. Inhibition of MEK-ERK signaling was achieved by injection of the MAPK/ERK kinase inhibitor U0126. The drug effectively improved cardiac function, decreased fibrosis, normalized heart size and increased probability of survival.
Conclusions: These results suggest that the 40 kD cMyBP-C fragment, which is produced at elevated levels during human cardiac disease, is a pathogenic fragment that is sufficient to cause hypertrophic cardiomyopathy and heart failure.
- myosin binding protein c
- mitogen activated protein kinase
- cardiac disease
- cardiac failure
- Received February 20, 2013.
- Revision received July 10, 2013.
- Accepted July 12, 2013.