Abstract: Objective To investigate the effect of stachydrine hydrochloride(Sta)on myocardial hypertrophy and the underlying mechanism.Methods C57BL/6 J mice were subjected to subcutaneous implantation of an osmotic pump for continuous administration of phenylephrine(PE)over 14 days and were orally treated with Sta.The small animal ultrasound imaging system was used to detect the cardiac function and structural parameters.HE staining and WGA staining were used to observe the morphological changes of heart and myocardial cells.The mRNA expression of cardiac hypertrophy biomarkers(ANP and BNP)was detected by RT-PCR.Cardiomyocytes were stimulated by PE to mimic hypertrophy,and the cells in the Sta group were treated with 5×10^-5 mol/L Sta for 48 h.Cytoskeleton was labeled with fluorescent dyes to measure cell surface,and the expression of fetal genes was detected by RT-PCR.Moreover,the activity of CaN was tested by ELISA.Calcium transient was detected by ion imaging system.The nuclear translocation of NFATc3 was detected by immunofluorescence.Dual-luciferase reporter assay was conducted to detect the GATA4 transcriptional activity.Results Compared with the sham group,the PE group exhibited an increase in ventricular wall thickness(values of IVSd,LVPWd,and LVPWs were elevated),a significant rise in the cardiac index,and a marked enlargement in the cross-sectional area of cardiomyocytes,accompanied by an upsurge in the mRNA expression levels of hypertrophy-related genes.Sta intervention notably attenuated the increase in these parameters induced by PE stimulation.Cellular experienments showed that cardiomyocytes stimulated with PE demonstrated increases in the cell surface and the expression levels of hypertrophy-related genes,and the increase of calcium transients caused the calcium dysregulation,resulting in an excessive activation of CaN enzyme activity,which in turn promoted the translocation of NFATc3 from the cytoplasm to the nucleus.PE stimulation also significantly enhanced the transcriptional activity of GATA4 in H9c2 cells.Sta intervention significantly inhibited the alterations induced by PE in cardiomyocytes.Conclusion Sta can effectively ameliorate PE-induced myocardial hypertrophy through modulation of the Ca²⁺/CaN/NFATc3/GATA4 signaling pathway.

Key words: stachydrine hydrochloride, cardiac hypertrophy, Ca²⁺/CaN/NFATc3/GATA4 signaling pathway