Tropomyosin Phosphorylation Plays a Crucial Role in Cardiac Remodeling and Re-remodeling

• Published in: The Thoracic and Cardiovascular Surgeon
• Main Authors: Schaefer, A., Schneeberger, Y., Stenzig, J., Schulz, S., Wieczorek, D., Schwoerer, A. P., Eschenhagen, T., Ehmke, H., Reichenspurner, H., Cuello, F.
• Format: Conference Proceeding
• Language: English
• Published: 20.01.2016
• ISSN: 0171-6425; 1439-1902
• DOI: 10.1055/s-0036-1571604

Background: Tropomyosin (Tm) is a thin-filament associated protein involved in the calcium dependent activation of cross-bridge cycling. It has been demonstrated previously that phosphorylation status of Tm impacts on the cardiac disease state in a humanized mouse model of hypertrophic cardiomyopathy (HCM). A reduction in Tm phosphorylation at Ser283 was shown to rescue the HCM phenotype, by restoring altered Ca 2+ sensitivity of the myofilaments and reducing the production of reactive oxygen species (ROS). How phosphorylation of Tm reflects disease progression in hypertrophic, failing and mechanical unloaded hearts remains elusive. Methods: To induce cardiac hypertrophy and heart failure, rats underwent transverse aortic constriction (TAC) surgery. Three and six weeks after TAC, heterotopic heart transplantation with hypertrophic and failing hearts was performed to induce mechanical unloading. Animals were sacrificed and grafts were explanted for determination of sarcomeric protein-phosphorylation levels by western immunoblotting. Results: Rat hearts showed significant hypertrophy (left ventricular surface: 8 ± 1.0 mm 2 versus 9.6 ± 2.4 mm 2 , p  = 0.026) and a tendency toward insufficiency (fractional shortening: 23.7 ± 4.3% versus 28.2 ± 1.5%, p  = 0.31) when compared with sham-operated hearts. Western immunoblotting revealed initially enhanced sarcomeric protein phosphorylation 3 weeks after TAC surgery for cardiac myosin-binding protein C (cMyBP-C), cardiac troponin I (cTnI) and phospholamban (PLN), which was attenuated 6 weeks after TAC. In contrast, Tm phosphorylation increased significantly in hypertrophic hearts and maintained high also in failing hearts. Tm phosphorylation was reversed to basal levels in response to mechanical unloading. Increased Tm phosphorylation during hypertrophy and heart failure development was paralleled by enhanced MEK-dependent and ERK-autophosphorylation, suggesting MAPK kinase involvement in this scenario. Conclusions: Tm phosphorylation reflects disease progression in cardiac remodeling and re-remodeling. Interestingly, Tm phosphorylation pattern during heart failure development is distinct from other known cardiac sarcomeric proteins, which show reduced phosphorylation in hypertrophic and failing hearts. Preliminary results suggest involvement of ROS-mediated MAPK kinase modulation in de- and phosphorylation of Tm. Final assertions regarding cause and effect as well as potential pharmacological modulation require further investigations.