Decreasing tropomyosin phosphorylation rescues tropomyosin-induced familial hypertrophic cardiomyopathy.

Abstract

Studies indicate that tropomyosin (Tm) phosphorylation status varies in different mouse models of cardiac disease. Investigation of basal and acute cardiac function utilizing a mouse model expressing an α-Tm protein that cannot be phosphorylated (S283A) shows a compensated hypertrophic phenotype with significant increases in SERCA2a expression and phosphorylation of phospholamban Ser-16 (Schulz, E. M., Correll, R. N., Sheikh, H. N., Lofrano-Alves, M. S., Engel, P. L., Newman, G., Schultz Jel, J., Molkentin, J. D., Wolska, B. M., Solaro, R. J., and Wieczorek, D. F. (2012) J. Biol. Chem. 287, 44478-44489). With these results, we hypothesized that decreasing α-Tm phosphorylation may be beneficial in the context of a chronic, intrinsic stressor. To test this hypothesis, we utilized the familial hypertrophic cardiomyopathy (FHC) α-Tm E180G model (Prabhakar, R., Boivin, G. P., Grupp, I. L., Hoit, B., Arteaga, G., Solaro, R. J., and Wieczorek, D. F. (2001) J. Mol. Cell. Cardiol. 33, 1815-1828). These FHC hearts are characterized by increased heart:body weight ratios, fibrosis, increased myofilament Ca(2+) sensitivity, and contractile defects. The FHC mice die by 6-8 months of age. We generated mice expressing both the E180G and S283A mutations and found that the hypertrophic phenotype was rescued in the α-Tm E180G/S283A double mutant transgenic animals; these mice exhibited no signs of cardiac hypertrophy and displayed improved cardiac function. These double mutant transgenic hearts showed increased phosphorylation of phospholamban Ser-16 and Thr-17 compared with the α-Tm E180G mice. This is the first study to demonstrate that decreasing phosphorylation of tropomyosin can rescue a hypertrophic cardiomyopathic phenotype.

• Authors: Emily M Schulz, Tanganyika Wilder, Shamim A K Chowdhury, Hajer N Sheikh, Beata M Wolska, R John Solaro, David F Wieczorek
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 40 Pg. 28925-35 (Oct 04 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23960072 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Mutant Proteins
• Tropomyosin
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Signaling
• Cardiomyopathy, Hypertrophic, Familial (diagnostic imaging, metabolism, pathology, physiopathology)
• Gene Expression Regulation
• Heart Function Tests
• Immunoblotting
• Mice
• Mice, Transgenic
• Mutant Proteins (metabolism)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (metabolism, pathology)
• Myofibrils (metabolism)
• Phosphorylation
• Tropomyosin (metabolism)
• Ultrasonography