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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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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DOI: https://doi.org/10.1007/s00210-007-0134-1