Objective To construct a transgenic model of HCM overexpressing cTnIR146W, observe the pathological change of this animal, and elucidate the signalling pathway involving in heart remodelling of cTnIR146W +/− mice.
Methods Cardiac hypertrophy-related signalling pathway protein, such as calcineurin, calsarcin-1, GSK-3β, AKT, SERCA2, PLB were detected by Western blot and RT-PCR. We also assessed the activity of calcineurin in cTnIR146W +/− mice, in order to elucidate potential mechanisms involving in the cardiac remodelling in cTnIR146W +/− mice.
Results The total expression of cTnI in cTnIR146W +/− mice was significant higher than cTnIR146W −/− mice (p<0.05), while the phosphorylation of cTnI decreased significantly (p<0.05), resulting in a obvious decrease of the ratio of phos-cTnI to cTnI (p<0.05). Pathological changes such as myocardial cell proliferation, cardiac hypertrophy, and interstitial fibrosis were observed by optical microscope in cTnIR146W +/− mice. Markers of cardiac hypertrophy, such as ANF, BNP, β-MHC increased significantly in cTnIR146W +/− mice (p<0.05). The expression of calsarcin-1 in cTnIR146W +/− mice was significantly higher than that of cTnIR146W −/− mice (p<0.01), while other cardiac hypertrophy-related signalling pathway protein, such as calcineurin, GSK-3β, AKT, SERCA2 did not change. The mRNA expression of PLB was reduced significantly by RT-PCR (p<0.05). Meanwhile, the calcineurin activity of cTnIR146W +/− mice increased significantly (p<0.01).
Conclusion cTnIR146W +/− mice had typical pathological cardiac remodelling and heart dysfunction, especially in the older ones. The expression of calsarcin-1 and the activity of calcineurin-NFAT signalling pathway may be the most important mechanism involving in pathological cardiac hypertrophy in cTnIR146W −/− mice.
- Hypertrophic cardiomyopathy (HCM)
- reverse transcription PCR (RT-PCR)
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