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Berberine Attenuates Ischemia-Reperfusion Injury Via Regulation of Adenosine-5′-monophosphate Kinase Activity in Both Non-ischemic and Ischemic Areas of the Rat Heart

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Abstract

Background

Berberine exhibits numerous pharmacological effects, but the mechanism for its protective effects against ischemia-reperfusion cardiac injury is unknown.

Methods

Male Wistar rats were treated with berberine (100 mg/Kg/day, ig) for 14 days and controls treated with water. Hearts were isolated in vitro and perfused in the Langendorff mode and subjected to 30 min of global ischemia followed by 30 min of reperfusion and hemodynamic data examined. In a separate set of experiments, hearts were subjected in vivo to left anterior descending coronary artery ligation for 30 min followed by 120 min reperfusion and hemodynamic data, type and duration of arrhythmias, and myocardial infarct size determined. AMP-activated protein kinase (AMPK) level, ADP/ATP and AMP/ATP ratios were examined in non-ischemic areas and risk areas of the heart.

Results

Subsequent to ischemia-reperfusion injury, left ventricular developed pressure, left ventricular end diastolic pressure and maximum rate of intraventricular pressure contractility and relaxation were significantly improved in the berberine treatment groups compared to controls. Berberine treatment decreased infarct size and diminished the duration and incidence of arrhythmias compared to controls. Berberine treatment significantly decreased AMPK protein concentration, and the ratio of ADP/ATP and AMP/ATP in the myocardial risk areas. In contrast, berberine treatment significantly increased AMPK protein concentration, and the ratio of ADP/ATP and AMP/ATP in the non-ischemia areas compared to controls.

Conclusion

These findings suggest that berberine may exert its cardioprotective effect on ischemia-reperfusion injury via regulation of AMPK activity in both non-ischemic areas and risk areas of the heart.

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Abbreviations

AAR:

area at risk

AICAR:

5-aminoimidazole-4-carboxamide -1-β-D-ribofuranoside

AMP:

adenosine monophosphate

ADP:

adenosine diphosphate

AMPK:

adenosine-5′-monophosphate kinase

AMPKK:

AMPK kinase

ATP:

adenosine triphosphate

BER:

berberine

CamKK:

calmodulin-dependent protein kinase

CDA:

coronary artery disease

−dp/dtmin:

+dp/dtmax, minimum and maximum rate of pressure change in the ventricle

ECG:

electrocardiogram

GAPDH:

glyceraldehydes-3-phosphate dehydrogenates

HR:

heart rate

IS:

infract size

KHB:

Krebs-Henseleit buffer

LKB1:

tumor suppressor kinase

LV:

left ventricular size

LVDP:

left ventricular developed pressure

LVEDP:

left ventricular end-diastolic pressure

NIA:

non-ischemia area

PBS:

phosphate buffered solution

TTC:

triphenyl tetrazolium chloride phosphate buffer

VAEs:

ventricular arrhythmic events

VF:

ventricular fibrillation

VT:

ventricular tachycardia.

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Acknowledgments

This work was supported by Jilin Science & Technology Development Plan (20070728-2, 20090441), Jilin Province Administration of Traditional Chinese medicine science and technology projects No.2010-093, Opening Project of State Key Laboratory of Supramolecular Structure and Materials of Jilin University under Grant No. SKLSSM200912, and the Heart and Stroke Foundation of Manitoba. G.M.H. is a Canada Research Chair in Molecular Cardiolipin Metabolism.

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Authors and Affiliations

  1. Department of Pharmacology, Norman Bethune Medical College, Jilin University, 126 Xin Min Street, Changchun, 130021, China

    Wenguang Chang, Ming Zhang, Jing Li, Zhaojie Meng, Dong Xiao, Shengnan Wei & Li Chen

  2. Department of Cadre Ward, First Affiliated Hospital of Jilin University, 71 Xin Min Street, Changchun, 130021, China

    ChunYan Wang

  3. Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, R3E 0T6, Canada

    Grant M. Hatch

  4. Department of Biochemistry & Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, R3E 0T6, Canada

    Grant M. Hatch

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  1. Wenguang Chang
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  2. Ming Zhang
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Correspondence to Li Chen or ChunYan Wang.

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Wenguang Chang and Ming Zhang contributed equally to this and was considered co-first author.

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Chang, W., Zhang, M., Li, J. et al. Berberine Attenuates Ischemia-Reperfusion Injury Via Regulation of Adenosine-5′-monophosphate Kinase Activity in Both Non-ischemic and Ischemic Areas of the Rat Heart. Cardiovasc Drugs Ther 26, 467–478 (2012). https://doi.org/10.1007/s10557-012-6422-0

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