Upregulation of leptin pathway correlates with abnormal expression of SERCA2a, phospholamban and the endothelin pathway in heart failure and reversal by CPU86017
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, ET(A)R, and ET(B)R mRNA expression in the myocardium. Protein expression of leptin and ET(A)R 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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Leptin adversely affects calcium handling in cardiomyocytes so as to impair myocardial relaxation, stimulates the synthesis of collagen inducing cardiac fibrosis by increasing aldosterone secretion, and enhances sodium tubular reabsorption.
“Moreover, leptin adversely affects calcium handling in cardiomyocytes so as to impair myocardial relaxation, stimulates the synthesis of collagen inducing cardiac fibrosis by increasing aldosterone secretion, and enhances the sodium tubular reabsorption [95,96,97].”
From Dysregulated epicardial adipose tissue as a risk factor and potential therapeutic target of heart failure with preserved ejection fraction in diabetes (2022) · cites this paper as [95]
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References 38 · Cited by 37
- Authors
- Na, T., Dai, D. Z., Tang, X. Y., & Dai, Y.
- Affiliations
- China Pharmaceutical University (CN)
- Corresponding author
- Dai, D. Z.
- ORCID
- Dai, Y.
- Venue
- Naunyn-Schmiedeberg s Archives of Pharmacology
- Published
- 2007-02-08
- Volume
- 375
- Issue
- 1
- Pages
- 39-49
- ISSN
- 0028-1298 (ISSN-L)
- 1432-1912
- OpenAlex
- W1974307847
- Cited by
- 37
- References
- 38
- Citations by year
- 2025: 4 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2014: 1 · 2013: 2 · 2012: 3
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Naunyn-Schmiedeberg s Archives of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- leptin, chronic heart failure, SERCA2a, phospholamban, endothelin pathway, cardiac remodeling, oxidative stress, reactive oxygen species, endothelin receptors, cardiac hypertrophy, hyperleptinemia, class III antiarrhythmic agents, antioxidant activity, cardiac contractility
- MeSH terms
- Endothelin-Converting Enzymes, Phospholamban, Animals, Anti-Arrhythmia Agents, Antioxidants, Berberine, Calcium-Binding Proteins, Creatine Kinase, Heart Failure, Heart Rate, L-Lactate Dehydrogenase, Male, Metalloendopeptidases, Myocardium, Up-Regulation, Gene Expression, Ventricular Function, Left, Aspartic Acid Endopeptidases, Rats, Sprague-Dawley, Receptors, Endothelin, Transferases (Other Substituted Phosphate Groups), Oxidative Stress, Endothelin-1, Alkyl and Aryl Transferases, Ventricular Remodeling, Leptin, Rats, Sarcoplasmic Reticulum Calcium-Transporting ATPases
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