Berberine Reverses Nitroglycerin Tolerance through Suppressing Protein Kinase C Alpha Activity in Vascular Smooth Muscle Cells

Purpose The aim of this study was to evaluate the effects of berberine on nitroglycerin (NTG) tolerance and explore the underlying mechanism involved. Methods NTG tolerance was induced by pre-exposure of Sprague-Dawley rat aortas to NTG in vitro or by pretreating Sprague-Dawley rats with an NTG patch in vivo. The aortas were pre-treated with berberine or PKC inhibitors for different durations of time before induction of NTG tolerance. NTG-induced vasorelaxations was measured on wire myograph. Primary vascular smooth cells (VSMCs) were used to dissect the underlying mechanism of berberine-induced inhibition of NTG tolerance. Results NTG tolerance induced by either prior exposure of rat aortas to NTG in vitro or pretreatment with an NTG patch in vivo was reversed by co-treatment with berberine, as well as the inhibitors of protein kinase C (PKC) and protein kinase C alpha (PKC alpha). The mechanistic study revealed that PKC alpha participated in the development of NTG tolerance as NTG increased the activity of PKC alpha with enriched PKC alpha membrane localization and elevated phosphorylation of PKC alpha in VSMCs, which was reversed by berberine or PKC alpha inhibitors. Conclusion This study is probably the first demonstration that berberine reverses NTG tolerance through inhibiting PKC alpha activity in VSMCs and PKC alpha is an important contributor to the development of NTG tolerance. These new findings suggest that berberine could become a promising drug for prevention of NTG tolerance and that targeting PKC alpha in VSMCs is likely to be a potential therapeutic strategy for reversal of NTG tolerance in blood vessels.

Automated summary

This study demonstrated that berberine reverses NTG tolerance by inhibiting PKC alpha activity in VSMCs. These findings suggest that berberine could be a promising drug for prevention of NTG tolerance and targeting PKC alpha in VSMCs may be a potential therapeutic strategy for reversal of NTG tolerance in blood vessels.