Cardioprotective effects of tanshinone IIA pretreatment via kinin B2 receptor-Akt-GSK-3β dependent pathway in experimental diabetic cardiomyopathy

Cardiovasc Diabetol. 2011 Jan 13;10:4. doi: 10.1186/1475-2840-10-4.

Abstract

Aims: Diabetic cardiomyopathy, characterized by myocardial structural and functional changes, is a specific cardiomyopathy develops in patients with diabetes mellitus. The present study was to investigate the role of kinin B2 receptor-Akt-glycogen synthase kinase (GSK)-3β signalling pathway in mediating the protective effects of tanshinone IIA (TSN) on diabetic cardiomyopathy.

Methods and results: Streptozocin (STZ) induced diabetic rats (n = 60) were randomized to receive TSN, TSN plus HOE140 (a kinin B2 receptor antagonist), or saline. Healthy Sprague-Dawley (SD) rats (n = 20) were used as control. Left ventricular function, myocardial apoptosis, myocardial ultrastructure, Akt, GSK-3β and NF-κB phosphorylation, the expression of TNF-α, IL-6 and myeloperoxidase (MPO) were examined. Cardiac function was well preserved as evidenced by increased left ventricular ejection fraction (LVEF) and ± dp/dt (maximum speed of contraction/relaxation), along with decreased myocardial apoptotic death after TSN administration. TSN pretreatment alleviated mitochondria ultrastructure changes. TSN also enhanced Akt and GSK-3β phosphorylation and inhibited NF-κB phosphorylation, resulting in decreased TNF-α, IL-6 and MPO activities. Moreover, pretreatment with HOE140 abolished the beneficial effects of TSN: a decrease in LVEF and ± dp/dt, an inhibition of cardiomyocyte apoptosis, a destruction of cardiomyocyte mitochondria cristae, a reduction of Akt and GSK-3β phosphorylation, an enhancement of NF-κB phosphorylation and an increase of TNF-α, IL-6 and MPO production.

Conclusion: These data indicated that TSN is cardioprotective in the context of diabetic cardiomyopathy through kinin B2 receptor-Akt-GSK-3β dependent pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abietanes / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Bradykinin / analogs & derivatives
  • Bradykinin / pharmacology
  • Cardiomyopathies / drug therapy*
  • Cardiomyopathies / enzymology
  • Cardiomyopathies / etiology
  • Cardiomyopathies / pathology
  • Cardiomyopathies / physiopathology
  • Cardiotonic Agents / pharmacology*
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / physiopathology
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Interleukin-6 / metabolism
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / enzymology
  • Myocardial Contraction / drug effects
  • Myocardium / enzymology*
  • Myocardium / ultrastructure
  • NF-kappa B / metabolism
  • Peroxidase / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Bradykinin B2 / drug effects*
  • Receptor, Bradykinin B2 / metabolism
  • Signal Transduction / drug effects
  • Stroke Volume / drug effects
  • Tumor Necrosis Factor-alpha / metabolism
  • Ventricular Function, Left / drug effects

Substances

  • Abietanes
  • Cardiotonic Agents
  • Interleukin-6
  • NF-kappa B
  • Receptor, Bradykinin B2
  • Tumor Necrosis Factor-alpha
  • tanshinone
  • icatibant
  • Peroxidase
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Bradykinin