There is increasing evidence that angiotensin II (Ang II) is associated with the cardiac electrical remodeling and thus the occurrence of ventricular arrhythmias under pathological conditions. Human ether-a-go-go-related gene (hERG) encodes the pore forming subunit of the channel underlying IKr, which is crucial for the repolarisation of cardiac action potentials. Our previous study has shown that Ang II produces an acute inhibitory effect on IKr/hERG currents via AT1 receptors in guinea pig ventricular myocytes. The present study was designed to investigate the post-transcription regulation of hERG channel protein by chronic stimulation of AT1 receptors in heterologous expression system. An HEK 293 cell line stably expressing hERG channels was established and human AT1 receptor was transiently co-transfected. Western-blot analysis showed that Ang II decreased the abundance of mature hERG protein (155-kDa) in a time- and dose-dependent manner without affecting the level of immature hERG protein (135-kDa). The relative intensity of mature 155-kDa band as control was 68 ± 4% after incubation of Ang II at 100 nM for 24 hours (P<0.01, n=6). Values are means ± S.E.M. of n experiments, compared by two-tailed Student’s t test. To investigate the effects of Ang II on degradation of mature hERG channels, we blocked forward trafficking with a Golgi transit inhibitor brefeldin A (BFA, 10 µM). Ang II significantly enhanced the time-dependent reduction of mature hERG channels. A proteasomal inhibitor lactacystin (5 µM) significantly inhibited Ang II-mediated reduction of the mature protein (from 67 ± 4% to 89 ± 3%, P<0.05, n=3), but the lysosomal inhibitor bafilomycin A1(1 µM) had no significant effect on the role of Ang II. It indicated that Ang II accelerated channel protein degradation, primarily through the proteasome pathway. The protein kinase C inhibitor bisindolylmaleimide I antagonized the reduction of mature 155-kDa proteins by Ang II, suggesting that the effect of Ang II was mediated by intracellular PKC signaling pathway. In conclusion, the chronic incubation of Ang II reduced the mature hERG channel protein by accelerating channel degradation through a PKC pathway. The findings suggest a potential mechanism by which elevated levels of Ang II may be involved in the hERG channel remodeling in heart diseases.