CPUY11018, an azimilide derivative, ameliorates isoproterenol-induced cardiac insufficiency through relieving dysfunctional mitochondria and endoplasmic reticulum
| Autor: | Rong-Hui Du, Meng Li, Humed Khan Hussein, De-Zai Dai, Yin Dai, Yi-Qun Tang, Fang-Hong Shi |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Cell Culture Techniques Down-Regulation Pharmaceutical Science Endoplasmic Reticulum Rats Sprague-Dawley Random Allocation chemistry.chemical_compound Downregulation and upregulation Internal medicine medicine Animals Myocyte Myocytes Cardiac Heart Failure Pharmacology NADPH oxidase Dose-Response Relationship Drug biology Hydantoins Endoplasmic reticulum Hemodynamics Hydrazones Isoproterenol Acetophenones NADPH Oxidases NOX4 Cardiovascular Agents Fibroblasts Mitochondria Rats Up-Regulation Oxidative Stress Endocrinology chemistry Cardiovascular agent Apocynin biology.protein P22phox Inflammation Mediators Carrier Proteins Reactive Oxygen Species Biomarkers |
| Zdroj: | Journal of Pharmacy and Pharmacology. 67:1029-1041 |
| ISSN: | 2042-7158 0022-3573 |
| DOI: | 10.1111/jphp.12401 |
| Popis: | ObjectivesDeterioration of cardiac performance under stress may be partly mediated by dysfunctional mitochondria and endoplasmic reticulum (ER) that is likely related to an activation of NADPH oxidase (NOX) and an increase in pro-inflammatory factors. We investigated if a new compound CPUY11018 (CPUY) derived from Azimilide could ameliorate the stress impaired cardiac performance.MethodsForty-eight male Sprague Dawley rats were randomly divided into six groups and were injected with isoproterenol (ISO, 1 ml/kg, s.c.) for 10 days. Cardiac myocytes and fibroblasts from neonate rats were incubated with ISO. CPUY was employed and compared with apocynin (APO) – an inhibitor of NOX.Key findingsIn ISO-treated group, the compromised haemodynamics and cardiac remodelling were significant with dysfunctional mitochondria indicated by decreased MnSOD and mitochondrial membrane potential, and an enhanced reactive oxygen species genesis. Downregulation of FKBP12.6, CASQ2 and SERCA2a was also remarkable in vivo and in vitro implying an abnormal ER. Upregulated Nox4, p22phox and p47phox were significant, associated with upregulation of Src, IκBβ and NFκB, and downregulation of pAMPK/AMPK and Cx40 in vivo and in vitro. These abnormalities were relieved by CPUY and APO.ConclusionsCPUY is potential in managing cardiac insufficiency through normalizing mitochondria and ER in the affected heart. |
| Databáze: | OpenAIRE |
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