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Upregulation of leptin pathway correlates with abnormal expression of SERCA2a, phospholamban and the endothelin pathway in heart failure and reversal by CPU86017

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Abstract

Emerging evidence indicates that leptin may be a potential new target in chronic heart failure (CHF) treatment. We hypothesized that hyperleptinemia may correlate with abnormal expression of SERCA2a, PLB (phospholamban), and the endothelin (ET) pathway in CHF. An activated ET pathway is involved in CHF that is suppressed by CPU86017 (p-chlorobenzyltetrahydroberberine chloride), a complex class III antiarrhythmic agent with an antioxidant effect. Thus, relief of CHF may be mediated by a reversal of abnormalities of the leptin system, the ET-reactive oxygen species (ROS) pathway, SERCA2a, and PLB by CPU86017. CHF was produced by coronary artery ligation for 6 weeks in rats. The rats were divided into 3 groups: sham, CHF untreated, and CHF+CPU86017 (4 mg/kg per day, s.c.). Hemodynamic changes, cardiac morphology, serum biochemistry, messenger ribonucleic acid (mRNA) and protein expression of the leptin pathway, ET pathway, and redox were measured. In CHF rats, hemodynamic abnormalities, cardiac remodeling, and histological changes with features of cardiac failure were associated with hyperlipidemia accompanied by oxidative stress and upregulated OB-Rb, ECE, pp-ET-1, ETAR, and ETBR mRNA expression in the myocardium. Protein expression of leptin and ETAR in the myocardium was markedly increased in CHF rats. An activated leptin pathway was associated with downregulation of SERCA2a and upregulation of PLB in mRNA and protein expression in CHF. CPU86017 downregulated the leptin system and reversed the above changes in the myocardium. An activated leptin pathway correlates with abnormal expression of SERCA2a and PLB and an activated ET-ROS system in the affected myocardium. The multi-ion-channel-blocking and antioxidative effects of CPU86017 downregulate the leptin pathway and ET system, resulting in reversal of the abnormalities of expression of SERCA2a and PLB and cardiac performance in CHF.

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Abbreviations

APD:

action potential duration

CAT:

catalase

CHF:

chronic heart failure

CPK:

creatine phosphokinase

ECE:

endothelin converting enzyme

ERK1/2 :

extracellular signal-regulated kinase1/2

ET:

endothelin

ET-1:

endothelin-1

ETAR:

endothelin type A receptor

ETBR:

endothelin type B receptor

GOT:

glutamic oxaloacetate transaminase

GPT:

glutamic pyruvate transaminase

GSH-px:

glutathione peroxidase

HE:

hematoxylin and eosin

HR:

heart rate

I Ca.L :

L-type calcium current

I Kr :

rapid delayed rectifier potassium channel

I Ks :

slow delayed-rectifier potassium current

JAK/STAT:

Janus kinase /signal transducer and activator of transcription

JNK:

Jun N-terminal kinase

LDH:

lactate dehydrogenase

LV:

left ventricle

LV+dP/dtmax:

maximal rate of LV systolic pressure

LV-dP/dtmin:

minimum rate of LV systolic pressure

LVEDP:

left ventricular end-diastolic pressure

LVSP:

left ventricular systolic pressure

MAPK:

mitogen-activated protein kinase

MDA:

malondialdehyde

NCX:

sodium calcium exchangers

PLB:

phospholamban

pp-ET-1:

prepro-ET-1

ROS:

reactive oxygen species

SAPK:

stress-activated protein kinase

SERCA2a:

sarco/endoplasmic reticulum ATPase 2a

SOD:

superoxide dismutase

SR:

sarcoplasmic reticulum

XOD:

xanthine oxidase

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Acknowledgement

This study is supported by projects No:30572193 and 30670760 from the National Natural Science of China. Professor David J. Triggle provided assistance with the composition and English styling of the paper.

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Authors and Affiliations

  1. Research Division of Pharmacology, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nangjing, People’s Republic of China

    T. Na, D. Z. Dai, X. Y. Tang & Y. Dai

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  1. T. Na
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  2. D. Z. Dai
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  3. X. Y. Tang
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Correspondence to D. Z. Dai.

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Na, T., Dai, D.Z., Tang, X.Y. et al. Upregulation of leptin pathway correlates with abnormal expression of SERCA2a, phospholamban and the endothelin pathway in heart failure and reversal by CPU86017. Naunyn-Schmied Arch Pharmacol 375, 39–49 (2007). https://doi.org/10.1007/s00210-007-0134-1

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