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

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.

• Authors: Dongdong Sun, Min Shen, Jiayi Li, Weijie Li, Yingmei Zhang, Li Zhao, Zheng Zhang, Yuan Yuan, Haichang Wang, Feng Cao
• Journal: Cardiovascular diabetology (Cardiovasc Diabetol) Vol. 10 Pg. 4 (Jan 13 2011) ISSN: 1475-2840 [Electronic] England
• PMID: 21232147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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