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

Abstract

The aim of the present study was to evaluate the effects of berberine on nitroglycerin (NTG) tolerance and explore the underlying mechanism involved. MethodsNTG tolerance was induced by pre-exposure of Sprague-Dawley rat aortas to NTG in vitro or by pretreating Sprague-Dawley rats with 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. ResultsNTG tolerance induced by either prior exposure of rat aortas to NTG in vitro or pretreatment with NTG patch in vivo was reversed by co-treatment with berberine, as well as the inhibitors of PKC and PKCα. The mechanistic study revealed that PKCα participated in the development of NTG tolerance as NTG increased the activity of PKCα with enriched PKCα membrane localization and elevated phosphorylation of PKCα in VSMCs, which was reversed by berberine or PKCα inhibitors. ConclusionThe present study is probably the rst demonstration that berberine reverses NTG tolerance through inhibiting PKCα activity in VSMCs and PKCα is an important contributor to the development of NTG tolerance. These new ndings suggest that berberine could become a promising drug for prevention of NTG tolerance and that targeting PKCα in VSMCs is likely to be a potential therapeutic target for reversal of NTG tolerance in blood vessels.

Effects of Berberine on Atherosclerosis

“…NO has a vasodilator function, so nitroglycerin has been used in clinical treatment for many CVDs, such as angina pectoris, congestive heart failure, and myocardial infarction. Berberine administration in rats could suppress protein kinase C-α in VSMCs to reverse nitroglycerin tolerance caused by long-term use (Zhang et al, 2021). All these results suggest that berberine may be latently available to prevent restenosis of arteries by inhibiting VSMCs proliferation.…”

“…Many traditional herbs inhibit the phenotype switching of VSMCs in atherosclerosis; examples include chocolate vine, garlic, and mountain asparagus (Saleh Al-Shehabi et al, 2016). Numerous studies have shown that berberine inhibited VSMCs proliferation and migration induced by multiple stimuli (Fatahian et al, 2020;Wu et al, 2020;Zhang et al, 2021), but whether berberine could inhibit the switching of VSMCs from contractile to synthetic phenotypes to reduce atherosclerosis has not been reported and must be explored.…”