Total triterpene acids, active ingredients from Fructus Corni, attenuate diabetic cardiomyopathy by normalizing ET pathway and expression of FKBP12.6 and SERCA2a in streptozotocin-rats.
Total triterpene acids (TTAs) isolated from Cornus officinalis Sieb., one of the herbs contained in Liuwei Dihuang decoction, were aimed at alleviating diabetic cardiomyopathy. We hypothesized that the benefits of TTAs may result from suppressing the endothelin-reactive oxidative species (ET-ROS) pathway in the myocardium. Diabetes was produced by a single injection of streptozotocin (STZ, 60 mg kg(-1), i.p.) in rats. Assessment of cardiac function, calcium handling proteins, endothelin-1 (ET-1) and redox system was conducted 8 weeks after STZ injection. Medication with TTAs (50 mg kg(-1), i.g.) was installed in the last 4 weeks. The compromised cardiac function was characterized by depressed contractility (LVSP and LV+dp/dt(max)) and relaxation (LVEDP and -LVdp/dt(min)) in association with hyperglycaemia (30.2 +/- 2.6 mmol L(-1)) in STZ-injected rats. Down-regulated expression of FKBP12.6 (calstabin 2), sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) and phospholamban (PLB) were also found. These changes occurred in connection with an increased ET-1, up-regulated mRNA of propreET-1 and endothelin converting enzyme (ECE), and a state of oxidant stress was found by increased malondialdehyde (MDA), decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activity, and an enhanced activity and expression of inducible nitric oxide synthase (iNOS) in the diabetic myocardium. After 4 weeks of treatment with TTAs, these changes were alleviated dramatically despite a mild reduction in hyperglycaemia (26.9 +/- 3.4 mmol L(-1)). In conclusion, TTAs, as active ingredients of Liuwei Dihuang decoction, alleviated diabetic cardiomyopathy by normalizing the abnormality of FKBP12.6 and SERCA2a and ET-ROS pathway in the myocardium rather than by hypoglycaemic activity.
Qi
Min-You
MY
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
Liu
Hao-Ran
HR
Dai
De-Zai
DZ
Li
Na
N
Dai
Yin
Y
D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology; D029768:Cornus / Q000737:chemistry*; D048909:Diabetes Complications / Q000188:drug therapy*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism; D013311:Streptozocin; D022021:Tacrolimus Binding Proteins / Q000187:drug effects / Q000378:metabolism; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*
D019332:Endothelin-1; D017382:Reactive Oxygen Species; D014315:Triterpenes; D013311:Streptozocin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B