Skip to main content
Erschienen in:

28.07.2021 | Original Article

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

verfasst von: Huina Zhang, Jinghui Dong, Chi-Wai Lau, Yu Huang

Erschienen in: Cardiovascular Drugs and Therapy | Ausgabe 4/2022

Einloggen, um Zugang zu erhalten

Abstract

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 (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.

Conclusion

This study is probably the first 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 findings 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 strategy for reversal of NTG tolerance in blood vessels.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
2.
Zurück zum Zitat Sage PR, de la Lande IS, Stafford I, Bennett CL, Phillipov G, Stubberfield J, et al. Nitroglycerin tolerance in human vessels: evidence for impaired nitroglycerin bioconversion. Circulation. 2000;102(23):2810–5.PubMedCrossRef Sage PR, de la Lande IS, Stafford I, Bennett CL, Phillipov G, Stubberfield J, et al. Nitroglycerin tolerance in human vessels: evidence for impaired nitroglycerin bioconversion. Circulation. 2000;102(23):2810–5.PubMedCrossRef
3.
Zurück zum Zitat Needleman P, Johnson EM Jr. Mechanism of tolerance development to organic nitrates. J Pharmacol Exp Ther. 1973;184(3):709–15.PubMed Needleman P, Johnson EM Jr. Mechanism of tolerance development to organic nitrates. J Pharmacol Exp Ther. 1973;184(3):709–15.PubMed
4.
Zurück zum Zitat Chen Z, Zhang J, Stamler JS. Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci U S A. 2002;99(12):8306–11.PubMedPubMedCentralCrossRef Chen Z, Zhang J, Stamler JS. Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci U S A. 2002;99(12):8306–11.PubMedPubMedCentralCrossRef
5.
Zurück zum Zitat Szocs K, Lassegue B, Wenzel P, Wendt M, Daiber A, Oelze M, et al. Increased superoxide production in nitrate tolerance is associated with NAD(P)H oxidase and aldehyde dehydrogenase 2 downregulation. J Mol Cell Cardiol. 2007;42(6):1111–8.PubMedCrossRef Szocs K, Lassegue B, Wenzel P, Wendt M, Daiber A, Oelze M, et al. Increased superoxide production in nitrate tolerance is associated with NAD(P)H oxidase and aldehyde dehydrogenase 2 downregulation. J Mol Cell Cardiol. 2007;42(6):1111–8.PubMedCrossRef
6.
Zurück zum Zitat Keith RA, Burkman AM, Sokoloski TD, Fertel RH. Vascular tolerance to nitroglycerin and cyclic GMP generation in rat aortic smooth muscle. J Pharmacol Exp Ther. 1982;221(3):525–31.PubMed Keith RA, Burkman AM, Sokoloski TD, Fertel RH. Vascular tolerance to nitroglycerin and cyclic GMP generation in rat aortic smooth muscle. J Pharmacol Exp Ther. 1982;221(3):525–31.PubMed
7.
Zurück zum Zitat Kim D, Rybalkin SD, Pi X, Wang Y, Zhang C, Munzel T, et al. Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance. Circulation. 2001;104(19):2338–43.PubMedCrossRef Kim D, Rybalkin SD, Pi X, Wang Y, Zhang C, Munzel T, et al. Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance. Circulation. 2001;104(19):2338–43.PubMedCrossRef
8.
Zurück zum Zitat Munzel T, Giaid A, Kurz S, Stewart DJ, Harrison DG. Evidence for a role of endothelin 1 and protein kinase C in nitroglycerin tolerance. Proc Natl Acad Sci U S A. 1995;92(11):5244–8.PubMedPubMedCentralCrossRef Munzel T, Giaid A, Kurz S, Stewart DJ, Harrison DG. Evidence for a role of endothelin 1 and protein kinase C in nitroglycerin tolerance. Proc Natl Acad Sci U S A. 1995;92(11):5244–8.PubMedPubMedCentralCrossRef
9.
10.
Zurück zum Zitat Harnett KM, Biancani P. Calcium-dependent and calcium-independent contractions in smooth muscles. Am J Med. 2003;115(Suppl 3A):24S–30S.PubMedCrossRef Harnett KM, Biancani P. Calcium-dependent and calcium-independent contractions in smooth muscles. Am J Med. 2003;115(Suppl 3A):24S–30S.PubMedCrossRef
11.
Zurück zum Zitat Kuo CL, Chi CW, Liu TY. The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett. 2004;203(2):127–37.PubMedCrossRef Kuo CL, Chi CW, Liu TY. The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett. 2004;203(2):127–37.PubMedCrossRef
12.
Zurück zum Zitat Jamshaid F, Dai J, Yang LX. New development of novel Berberine derivatives against bacteria. Mini Rev Med Chem. 2020;20(8):716–24.PubMedCrossRef Jamshaid F, Dai J, Yang LX. New development of novel Berberine derivatives against bacteria. Mini Rev Med Chem. 2020;20(8):716–24.PubMedCrossRef
13.
Zurück zum Zitat Zhang H, Wei J, Xue R, Wu JD, Zhao W, Wang ZZ, et al. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism. 2010;59(2):285–92.PubMedCrossRef Zhang H, Wei J, Xue R, Wu JD, Zhao W, Wang ZZ, et al. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism. 2010;59(2):285–92.PubMedCrossRef
14.
Zurück zum Zitat Zan Y, Kuai CX, Qiu ZX, Huang F. Berberine ameliorates diabetic neuropathy: TRPV1 modulation by PKC pathway. Am J Chinese Med. 2017;45(8):1709–23.CrossRef Zan Y, Kuai CX, Qiu ZX, Huang F. Berberine ameliorates diabetic neuropathy: TRPV1 modulation by PKC pathway. Am J Chinese Med. 2017;45(8):1709–23.CrossRef
15.
Zurück zum Zitat Liu JW, Abidi P, Kong WJ, Jiang JD. Berberine is a promising novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Circulation. 2004;110(17):144. Liu JW, Abidi P, Kong WJ, Jiang JD. Berberine is a promising novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Circulation. 2004;110(17):144.
16.
Zurück zum Zitat Li MH, Zhang YJ, Yu YH, Yang SH, Iqbal J, Mi QY, et al. Berberine improves pressure overload-induced cardiac hypertrophy and dysfunction through enhanced autophagy. Eur J Pharmacol. 2014;728:67–76.PubMedCrossRef Li MH, Zhang YJ, Yu YH, Yang SH, Iqbal J, Mi QY, et al. Berberine improves pressure overload-induced cardiac hypertrophy and dysfunction through enhanced autophagy. Eur J Pharmacol. 2014;728:67–76.PubMedCrossRef
17.
Zurück zum Zitat Li XX, Li CB, Xiao J, Gao HQ, Wang HW, Zhang XY, et al. Berberine attenuates vascular remodeling and inflammation in a rat model of metabolic syndrome. Biol Pharm Bull. 2015;38(6):862–8.PubMedCrossRef Li XX, Li CB, Xiao J, Gao HQ, Wang HW, Zhang XY, et al. Berberine attenuates vascular remodeling and inflammation in a rat model of metabolic syndrome. Biol Pharm Bull. 2015;38(6):862–8.PubMedCrossRef
18.
Zurück zum Zitat Wang J, Guo T, Peng QS, Yue SW, Wang SX. Berberine via suppression of transient receptor potential vanilloid 4 channel improves vascular stiffness in mice. J Cell Mol Med. 2015;19(11):2607–16.PubMedPubMedCentralCrossRef Wang J, Guo T, Peng QS, Yue SW, Wang SX. Berberine via suppression of transient receptor potential vanilloid 4 channel improves vascular stiffness in mice. J Cell Mol Med. 2015;19(11):2607–16.PubMedPubMedCentralCrossRef
19.
Zurück zum Zitat Huang Z, Han Z, Ye B, Dai Z, Shan P, Lu Z, et al. Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes. Eur J Pharmacol. 2015;762:1–10.PubMedCrossRef Huang Z, Han Z, Ye B, Dai Z, Shan P, Lu Z, et al. Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes. Eur J Pharmacol. 2015;762:1–10.PubMedCrossRef
20.
Zurück zum Zitat Ko WH, Yao XQ, Lau CW, Law WI, Chen ZY, Kwok W, et al. Vasorelaxant and antiproliferative effects of berberine. Eur J Pharmacol. 2000;399(2–3):187–96.PubMedCrossRef Ko WH, Yao XQ, Lau CW, Law WI, Chen ZY, Kwok W, et al. Vasorelaxant and antiproliferative effects of berberine. Eur J Pharmacol. 2000;399(2–3):187–96.PubMedCrossRef
21.
Zurück zum Zitat Yung LM, Wong WT, Tian XY, Leung FP, Yung LH, Chen ZY, et al. Inhibition of renin-angiotensin system reverses endothelial dysfunction and oxidative stress in estrogen deficient rats. PLoS One. 2011;6(3):e17437.PubMedPubMedCentralCrossRef Yung LM, Wong WT, Tian XY, Leung FP, Yung LH, Chen ZY, et al. Inhibition of renin-angiotensin system reverses endothelial dysfunction and oxidative stress in estrogen deficient rats. PLoS One. 2011;6(3):e17437.PubMedPubMedCentralCrossRef
22.
Zurück zum Zitat Li L, Zhang HN, Chen HZ, Gao P, Zhu LH, Li HL, et al. SIRT1 acts as a modulator of Neointima formation following vascular injury in mice. Circ Res. 2011;108(10):1180–U95.PubMedCrossRef Li L, Zhang HN, Chen HZ, Gao P, Zhu LH, Li HL, et al. SIRT1 acts as a modulator of Neointima formation following vascular injury in mice. Circ Res. 2011;108(10):1180–U95.PubMedCrossRef
23.
Zurück zum Zitat Seki T, Matsubayashi H, Amano T, Shirai Y, Saito N, Sakai N. Phosphorylation of PKC activation loop plays an important role in receptor-mediated translocation of PKC. Genes Cells. 2005;10(3):225–39.PubMedCrossRef Seki T, Matsubayashi H, Amano T, Shirai Y, Saito N, Sakai N. Phosphorylation of PKC activation loop plays an important role in receptor-mediated translocation of PKC. Genes Cells. 2005;10(3):225–39.PubMedCrossRef
24.
Zurück zum Zitat Munzel T. Does nitroglycerin therapy hit the endothelium? J Am Coll Cardiol. 2001;38(4):1102–5.PubMed Munzel T. Does nitroglycerin therapy hit the endothelium? J Am Coll Cardiol. 2001;38(4):1102–5.PubMed
25.
Zurück zum Zitat Munzel T, Li H, Mollnau H, Hink U, Matheis E, Hartmann M, et al. Effects of long-term nitroglycerin treatment on endothelial nitric oxide synthase (NOS III) gene expression, NOS III-mediated superoxide production, and vascular NO bioavailability. Circ Res. 2000;86(1):E7–E12.PubMedCrossRef Munzel T, Li H, Mollnau H, Hink U, Matheis E, Hartmann M, et al. Effects of long-term nitroglycerin treatment on endothelial nitric oxide synthase (NOS III) gene expression, NOS III-mediated superoxide production, and vascular NO bioavailability. Circ Res. 2000;86(1):E7–E12.PubMedCrossRef
26.
Zurück zum Zitat Hinz B, Schroder H. Vitamin C attenuates nitrate tolerance independently of its antioxidant effect. FEBS Lett. 1998;428(1–2):97–9.PubMedCrossRef Hinz B, Schroder H. Vitamin C attenuates nitrate tolerance independently of its antioxidant effect. FEBS Lett. 1998;428(1–2):97–9.PubMedCrossRef
27.
Zurück zum Zitat Laight DW, Carrier MJ, Anggard EE. Investigation of role for oxidant stress in vascular tolerance development to glyceryl trinitrate in vitro. Br J Pharmacol. 1997;120(8):1477–82.PubMedPubMedCentralCrossRef Laight DW, Carrier MJ, Anggard EE. Investigation of role for oxidant stress in vascular tolerance development to glyceryl trinitrate in vitro. Br J Pharmacol. 1997;120(8):1477–82.PubMedPubMedCentralCrossRef
28.
Zurück zum Zitat Tsou PS, Addanki V, Fung HL. Dissociation between superoxide accumulation and nitroglycerin-induced tolerance. J Pharmacol Exp Ther. 2008;327(1):97–104.PubMedCrossRef Tsou PS, Addanki V, Fung HL. Dissociation between superoxide accumulation and nitroglycerin-induced tolerance. J Pharmacol Exp Ther. 2008;327(1):97–104.PubMedCrossRef
29.
Zurück zum Zitat Wang EQ, Lee WI, Fung HL. Lack of critical involvement of endothelial nitric oxide synthase in vascular nitrate tolerance in mice. Br J Pharmacol. 2002;135(2):299–302.PubMedPubMedCentralCrossRef Wang EQ, Lee WI, Fung HL. Lack of critical involvement of endothelial nitric oxide synthase in vascular nitrate tolerance in mice. Br J Pharmacol. 2002;135(2):299–302.PubMedPubMedCentralCrossRef
30.
Zurück zum Zitat Chandirasegaran G, Elanchezhiyan C, Ghosh K, Sethupathy S. Berberine chloride ameliorates oxidative stress, inflammation and apoptosis in the pancreas of Streptozotocin induced diabetic rats. Biomed Pharmacother. 2017;95:175–85.PubMedCrossRef Chandirasegaran G, Elanchezhiyan C, Ghosh K, Sethupathy S. Berberine chloride ameliorates oxidative stress, inflammation and apoptosis in the pancreas of Streptozotocin induced diabetic rats. Biomed Pharmacother. 2017;95:175–85.PubMedCrossRef
31.
Zurück zum Zitat Kim S, Han J, Lee SK, Choi MY, Kim J, Lee J, et al. Berberine suppresses the TPA-induced MMP-1 and MMP-9 expressions through the inhibition of PKC-alpha in breast Cancer cells. J Surg Res. 2012;176(1):E21–E9.PubMedCrossRef Kim S, Han J, Lee SK, Choi MY, Kim J, Lee J, et al. Berberine suppresses the TPA-induced MMP-1 and MMP-9 expressions through the inhibition of PKC-alpha in breast Cancer cells. J Surg Res. 2012;176(1):E21–E9.PubMedCrossRef
32.
Zurück zum Zitat Kong WJ, Zhang H, Song DQ, Xue R, Zhao W, Wei J, et al. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin. Receptor expression. Metab-Clin Experimental. 2009;58(1):109–19.CrossRef Kong WJ, Zhang H, Song DQ, Xue R, Zhao W, Wei J, et al. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin. Receptor expression. Metab-Clin Experimental. 2009;58(1):109–19.CrossRef
33.
Zurück zum Zitat Daniel TA, Nawarskas JJ. Vitamin C in the prevention of nitrate tolerance. Ann Pharmacother. 2000;34(10):1193–7.PubMedCrossRef Daniel TA, Nawarskas JJ. Vitamin C in the prevention of nitrate tolerance. Ann Pharmacother. 2000;34(10):1193–7.PubMedCrossRef
34.
Zurück zum Zitat Minamiyama Y, Takemura S, Hai S, Suehiro S, Okada S. Vitamin E deficiency accelerates nitrate tolerance via a decrease in cardiac P450 expression and increased oxidative stress. Free Radic Biol Med. 2006;40(5):808–16.PubMedCrossRef Minamiyama Y, Takemura S, Hai S, Suehiro S, Okada S. Vitamin E deficiency accelerates nitrate tolerance via a decrease in cardiac P450 expression and increased oxidative stress. Free Radic Biol Med. 2006;40(5):808–16.PubMedCrossRef
35.
Zurück zum Zitat Boesgaard S, Nielsen-Kudsk JE, Laursen JB, Aldershvile J. Thiols and nitrates: Reevaluation of the thiol depletion theory of nitrate tolerance. Am J Cardiol. 1998;81(1a):21a–9a.CrossRef Boesgaard S, Nielsen-Kudsk JE, Laursen JB, Aldershvile J. Thiols and nitrates: Reevaluation of the thiol depletion theory of nitrate tolerance. Am J Cardiol. 1998;81(1a):21a–9a.CrossRef
36.
Zurück zum Zitat Daiber A, Mulsch A, Hink U, Mollnau H, Warnholtz A, Oelze M, et al. The oxidative stress concept of nitrate tolerance and the antioxidant properties of hydralazine. Am J Cardiol. 2005;96(7B):25i–36i.PubMedCrossRef Daiber A, Mulsch A, Hink U, Mollnau H, Warnholtz A, Oelze M, et al. The oxidative stress concept of nitrate tolerance and the antioxidant properties of hydralazine. Am J Cardiol. 2005;96(7B):25i–36i.PubMedCrossRef
37.
Zurück zum Zitat Parker JO, Parker JD, Caldwell RW, Farrell B, Kaesemeyer WH. The effect of supplemental L-arginine on tolerance development during continuous transdermal nitroglycerin therapy. J Am Coll Cardiol. 2002;39(7):1199–203.PubMedCrossRef Parker JO, Parker JD, Caldwell RW, Farrell B, Kaesemeyer WH. The effect of supplemental L-arginine on tolerance development during continuous transdermal nitroglycerin therapy. J Am Coll Cardiol. 2002;39(7):1199–203.PubMedCrossRef
38.
Zurück zum Zitat El-Demerdash E. Evidences for prevention of nitroglycerin tolerance by carvedilol. Pharmacol Res. 2006;53(4):380–5.PubMedCrossRef El-Demerdash E. Evidences for prevention of nitroglycerin tolerance by carvedilol. Pharmacol Res. 2006;53(4):380–5.PubMedCrossRef
39.
Zurück zum Zitat Liu CQ, Leung FP, Lee VW, Lau CW, Yao X, Lu L, et al. Prevention of nitroglycerin tolerance in vitro by T0156, a selective phosphodiesterase type 5 inhibitor. Eur J Pharmacol. 2008;590(1–3):250–4.PubMedCrossRef Liu CQ, Leung FP, Lee VW, Lau CW, Yao X, Lu L, et al. Prevention of nitroglycerin tolerance in vitro by T0156, a selective phosphodiesterase type 5 inhibitor. Eur J Pharmacol. 2008;590(1–3):250–4.PubMedCrossRef
40.
Zurück zum Zitat Gupta D, Georgiopoulou VV, Kalogeropoulos AP, Marti CN, Yancy CW, Gheorghiade M, et al. Nitrate therapy for heart failure: benefits and strategies to overcome tolerance. JACC Heart Fail. 2013;1(3):183–91.PubMedCrossRef Gupta D, Georgiopoulou VV, Kalogeropoulos AP, Marti CN, Yancy CW, Gheorghiade M, et al. Nitrate therapy for heart failure: benefits and strategies to overcome tolerance. JACC Heart Fail. 2013;1(3):183–91.PubMedCrossRef
41.
Zurück zum Zitat Mohanty N, Wasserman AG, Walker P, Katz RJ. Prevention of nitroglycerin tolerance with diuretics. Am Heart J. 1995;130(3 Pt 1):522–7.PubMedCrossRef Mohanty N, Wasserman AG, Walker P, Katz RJ. Prevention of nitroglycerin tolerance with diuretics. Am Heart J. 1995;130(3 Pt 1):522–7.PubMedCrossRef
Metadaten
Titel
Berberine Reverses Nitroglycerin Tolerance through Suppressing Protein Kinase C Alpha Activity in Vascular Smooth Muscle Cells
verfasst von
Huina Zhang
Jinghui Dong
Chi-Wai Lau
Yu Huang
Publikationsdatum
28.07.2021
Verlag
Springer US
Erschienen in
Cardiovascular Drugs and Therapy / Ausgabe 4/2022
Print ISSN: 0920-3206
Elektronische ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-021-07193-z

Weitere Artikel der Ausgabe 4/2022

Cardiovascular Drugs and Therapy 4/2022 Zur Ausgabe

Neu im Fachgebiet Kardiologie

Herzrhythmusstörungen – neue Verfahren für langfristige Erfolge

16.07.2024 Vorhofflimmern Podcast

Prof. Markus Lerch wirft gemeinsam mit dem Herzspezialisten Prof. Gerd Hasenfuß aus Göttingen einen Blick auf neue Entwicklungen in der Diagnostik und Therapie von Herzrhythmusstörungen. Hören Sie in dieser Folge, warum fast jedes Vorhofflimmern therapiert werden sollte, wieso die Ablationsbehandlung auch bei Herzinsuffizienz gute Effekte zeigt und vor und nach welchen Medikamenten Sie ein EKG schreiben sollten.

Deutsche Gesellschaft für Innere Medizin

Kongestive Herzinsuffizienz: Wie die Diurese am besten gelingt

15.07.2024 Herzinsuffizienz Nachrichten

Ein effektives Flüssigkeitsmanagement ist bei schwerer kongestiver Herzinsuffizienz essenziell. Ein gutes Therapieregime im ambulanten Setting scheint die Kombination aus Furosemid und Metolazon zu sein; im Vergleich gelang damit die stärkste Natriurese.

Vorhofflimmern: Auftreten schon in jüngeren Jahren ist kein gutes Zeichen

15.07.2024 Vorhofflimmern Nachrichten

Tritt Vorhofflimmern schon in jüngeren Jahren auf, geht dies mit einem höheren Risiko für kardiovaskuläre Erkrankungen und einer verkürzten Lebenserwartung einher, zeigt eine landesweite Studie aus Dänemark.

Bempedoinsäure bei gleicher LDL-Senkung klinisch so wirksam wie Statine

15.07.2024 Lipidstoffwechselstörungen Nachrichten

Der Lipidsenker Bempedoinsäure reduziert das Risiko für kardiovaskuläre Ereignisse pro Senkung des LDL-Cholesterins um 1 mmol/l ebenso wirksam wie Statine, so das Ergebnis eines indirekten Vergleichs beider Therapien.

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.