The Effects And Mechanism Of Calcineurin Signal Transduction Pathway In Urotensin â…¡-induced Cardiomyocyte Hypertrophy

Objective:Cardiomyocyte hypertrophy is not only a significant predictor of sudden death of cardiovascular diseases, but also an important risk factor of heart failure. As a result, it is of great importance to study the mechanisms of cardiac hypertrophy. Recently, some studies have fond that Urotensin II (UII) can induce cardiomyocyte hypertrophy, but the causes and mechanisms are not very clear. Other studies have shown that calcineurin (CaN)-mediated signal pathway plays a key role in pressure overload induced cardiac hypertrophy, and it is an important upstream regulatory mechanism during cardiac hypertrophy. In this article, we investigated the relationship between Calcineurin and Urotensin II in cardiac hypertrophy induced by UII.Methods :①Neonatal rat cardiomyocytes were prepared.②The changes of morphology, DNA and protein in cardiomyocytes were observed using Real time-PCR and Western blot techniques. The changes of calcineurin signal transduction pathway related molecules and proteins in the process of cardiac hypertrophy were observed.③The change of intracellular Ca2+ concentration in MC intervened with UII, nicardipine and xestospongin was investigated using fluorescent probes labeling technique.Results:①The expressions ofβ-MHC, CaN and P-ERK mRNA and protein in MC could be induced by UII in a concentration-dependent manner. In the group treated with 10-8and 10-7mol/L UII, the expressions ofβ-MHC, CaN and P-ERK mRNA and protein are significantly higher than that of control group (P<0.05).②The increases ofβ-MHC, CaN and P-ERK mRNA and protein induced by UII are time-dependent. Cardiomyocytes pretreated with 10-8mol/L UII for 12-48h could induce a time-dependent increases in the expressions ofβ-MHC, CaN and P-ERK mRNA and protein (P<0.05).③UII-induced upregulation ofβ-MHC, CaN and P-ERK mRNA and protein could be partly abolished after pretreated with cyclosporine A for 24h (P<0.05).④A rapid increase of intracellular Ca2+ in MC was observed shortly after the treatment of 10-8mol/L UII.⑤UII-induced elevation of intracellular free Ca2+ concentration in MC could be partly abolished after pretreated with nicardipine.⑥The elevation of intracellular free Ca2+ concentration in MC pretreated with xestospongin C could obviously be inhibited.Conclusion:①Calcineurin-mediated signal pathway may play a key role in UII -induced cardiac hypertrophy. In the process of cardiac hypertrophy, the expression of CaN could be induced by UII in a time and concentration-dependent manner in MC, and this effect can be attenuated by CSA.②There is a "cross-talk" relationship between CaN signal transduction pathway and the MAPK signal transduction pathway.③UII increases the intracellular Ca2+ level in MC, which mainly through two aspects: extracellular calcium influxes and calcium in the sarcoplasmic reticulum releases.