AdipoRon, the first orally active adiponectin receptor activator, attenuates postischemic myocardial apoptosis through both AMPK-mediated and AMPK-independent signalings
Open accessAbstract
Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The current study investigated whether AdipoRon, the first orally active molecule that binds APN receptors, may protect the heart against MI/R injury, and if so, to delineate the involved mechanisms. Wild-type (WT), APN knockout (APN-KO), and cardiomyocyte specific-AMPK dominant negative (AMPK-DN) mice were treated with vehicle or AdipoRon (50 mg/kg, 10 min prior to MI) and subjected to MI/R (30 min/3-24 h). Compared with vehicle, oral administration of AdipoRon to WT mice significantly improved cardiac function and attenuated postischemic cardiomyocyte apoptosis, determined by DNA ladder formation, TUNEL staining, and caspase-3 activation (all P < 0.01). MI/R-induced apoptotic cell death was significantly enhanced in mice deficient in either APN (APN-KO) or AMPK (AMPK-DN). In APN-KO mice, AdipoRon attenuated MI/R injury to the same degree as observed in WT mice. In AMPK-DN mice, AdipoRon's antiapoptotic action was partially inhibited but not lost. Finally, AdipoRon significantly attenuated postischemic oxidative stress, as evidenced by reduced NADPH oxidase expression and superoxide production. Collectively, these results demonstrate for the first time that AdipoRon, an orally active APN receptor activator, effectively attenuated postischemic cardiac injury, supporting APN receptor agonists as a promising novel therapeutic approach treating cardiovascular complications caused by obesity-related disorders such as type 2 diabetes.
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AdipoRon has been proposed for treatment of type 2 diabetes and other obesity-related disorders in mice.
“AdipoRon has first been proposed for the treatment of type 2 diabetes and other obesity-related disorders in mice [32,106,107,108,137,138].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [138]
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- Authors
- Zhang, Y., Zhao, J., Li, R., Lau, W. B., Yuan, Y.-X., Liang, B., Li, R., Gao, E.-H., Koch, W. J., Ma, X.-L., & Wang, Y.-J.
- Affiliations
- Shanxi Medical University (CN)
- Thomas Jefferson University (US)
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; and
- Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania
- Temple University (US)
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China;
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2015-08-01
- Volume
- 309
- Issue
- 3
- Pages
- E275-E282
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC4525114
- OpenAlex
- W1813598419
- Cited by
- 97
- References
- 38
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 8 · 2023: 4 · 2022: 13 · 2021: 10 · 2020: 11 · 2019: 13 · 2018: 7 · 2017: 17 · 2016: 7 · 2015: 1
- FWCI
- 8.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Medicine Forum (submittedVersion)
- Funders
- NIH (HL-123404, HL-096686)
- American Diabetes Association (ADA) (7-11-BS-93, 1-14-BS-228)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- AdipoRon, adiponectin receptor agonist, myocardial ischemia-reperfusion injury, cardiomyocyte apoptosis, AMPK signaling, oxidative stress, NADPH oxidase, superoxide, type 2 diabetes, obesity, cardioprotection
- MeSH terms
- Administration, Oral, Animals, Cardiotonic Agents, Heart Ventricles, Hypoglycemic Agents, Male, Mice, Transgenic, Piperidines, Random Allocation, Signal Transduction, Myocardial Reperfusion Injury, Myocardial Ischemia, Apoptosis, Mice, Knockout, Oxidative Stress, Mutant Proteins, Adiponectin, Receptors, Adiponectin, AMP-Activated Protein Kinases
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