title: Berberine Pretreatment Confers Cardioprotection Against Ischemia-Reperfusion Injury in a Rat Model of Type 2 Diabetes.
abstract: Preclinical and clinical studies have demonstrated that berberine (BBR) improves diabetic complications and reduces mortality of patients with congestive heart failure. The therapeutic effects of BBR have been reported to be mediated by its regulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). We previously reported that BBR protects against ischemia-reperfusion injury via regulating AMPK activity in both ischemic and nonischemic areas of the rat heart. Since diabetic hearts are more sensitive to ischemia-reperfusion injury, we examined whether BBR treatment exhibited cardioprotective effects in the diabetic heart. Type 2 diabetic rats were pretreated plus or minus BBR for 7 days and subjected to 30-minute ischemia followed by 120-minute reperfusion. Pretreatment of type 2 diabetic rats with BBR reduced ischemia-reperfusion injury infarct size and attenuated arrhythmia compared to untreated diabetic controls. Subsequent to ischemia-reperfusion, serum triglyceride, total cholesterol, and malondialdehyde levels were reduced by pretreatment of type 2 diabetic rats with BBR compared to untreated diabetic controls. In contrast, serum glucose and superoxide dismutase levels were unaltered. The mechanism for the BBR-mediated cardioprotective effect was examined. Pretreatment with BBR did not alter AMPK activity in ischemic areas at risk but increased AMPK activity in nonischemic areas compared to untreated diabetic controls. The increased AMPK activity in nonischemic areas was due an elevated ratio of AMP to adenosine triphosphate (ATP) and adenosine diphosphate to ATP. In addition, pretreatment with BBR increased protein kinase B (AKT) phosphorylation and reduced glycogen synthase kinase 3β (GSK3β) activity in nonischemic areas compared to untreated diabetic controls. These findings indicate that BBR protects the diabetic heart from ischemia-reperfusion injury. In addition, BBR may mediate this cardioprotective effect through AMPK activation, AKT phosphorylation, and GSK3β inhibition in the nonischemic areas of the diabetic heart.
authors: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China Department of Pharmacology and Therapeutics, Center for Research and Treatment of Atherosclerosis, University of Manitoba, Winnipeg, Manitoba, Canada DREAM Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada.
authors: Wenguang
authors: W
authors: Chang
authors: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China.
authors: Kun
authors: K
authors: Li
authors: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China.
authors: Fengying
authors: F
authors: Guan
authors: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China.
authors: Fan
authors: F
authors: Yao
authors: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China.
authors: Yang
authors: Y
authors: Yu
authors: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China Department of Pharmacology and Therapeutics, Center for Research and Treatment of Atherosclerosis, University of Manitoba, Winnipeg, Manitoba, Canada DREAM Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada chensubmit@126.com.
authors: Ming
authors: M
authors: Zhang
authors: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China Department of Pharmacology and Therapeutics, Center for Research and Treatment of Atherosclerosis, University of Manitoba, Winnipeg, Manitoba, Canada DREAM Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada Department of Biochemistry and Medical Genetics, Center for Research and Treatment of Atherosclerosis, University of Manitoba, Winnipeg, Manitoba, Canada.
authors: Grant M
authors: GM
authors: Hatch
authors: Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China.
authors: Li
authors: L
authors: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control; D001599:Berberine / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D058065:Diabetic Cardiomyopathies / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D002317:Cardiovascular Agents; D008055:Lipids; D001599:Berberine; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases
keywords: AMPK; berberine; heart; ischemia–reperfusion; type 2 diabetes