N-n-butyl haloperidol iodide protects cardiomyocytes against hypoxia/reoxygenation injury by inhibiting autophagy.

Abstract

N-n-butyl haloperidol iodide (F2), a novel compound derived from haloperidol, protects against the damaging effects of ischemia/reperfusion (I/R) injury in vitro and in vivo. In this study, we hypothesized the myocardial protection of F2 on cardiomyocyte hypoxia/reoxygenation (H/R) injury is mediated by inhibiting autophagy in H9c2 cells. The degree of autophagy by treatment with F2 exposed to H/R in H9c2 cell was characterized by monodansylcadaverine, transmission electron microscopy, and expression of autophagy marker protein LC3. Our results indicated that treatment with F2 inhibited autophagy in H9c2 cells exposed to H/R. 3-methyladenine, an inhibitor of autophagy, suppressed H/R-induced autophagy, and decreased apoptosis, whereas rapamycin, a classical autophagy sensitizer, increased autophagy and apoptosis. Mechanistically, macrophage migration inhibitory factor (MIF) was inhibited by F2 treatment after H/R. Accordingly, small interfering RNA (siRNA)-mediated MIF knockdown decreased H/R-induced autophagy. In summary, F2 protects cardiomyocytes during H/R injury through suppressing autophagy activation. Our results provide a new mechanistic insight into a functional role of F2 against H/R-induced cardiomyocyte injury and death.

• Authors: Bin Wang, Shuping Zhong, Fuchun Zheng, Yanmei Zhang, Fenfei Gao, Yicun Chen, Binger Lu, Han Xu, Ganggang Shi
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 28 Pg. 24709-21 (Sep 22 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26359352 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• LC3 protein, rat
• Macrophage Migration-Inhibitory Factors
• Microtubule-Associated Proteins
• N-n-butyl haloperidol iodide
• Protective Agents
• 3-methyladenine
• mTOR protein, rat
• TOR Serine-Threonine Kinases
• Intramolecular Oxidoreductases
• Mif protein, rat
• monodansylcadaverine
• Haloperidol
• Adenine
• Cadaverine
• Sirolimus

Topics

• Adenine (analogs & derivatives, pharmacology)
• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cadaverine (analogs & derivatives, metabolism)
• Cell Line
• Cytoprotection
• Dose-Response Relationship, Drug
• Haloperidol (analogs & derivatives, pharmacology)
• Intramolecular Oxidoreductases (genetics, metabolism)
• Macrophage Migration-Inhibitory Factors (genetics, metabolism)
• Microtubule-Associated Proteins (metabolism)
• Myocardial Reperfusion Injury (genetics, metabolism, pathology, prevention & control)
• Myocytes, Cardiac (drug effects, metabolism, pathology, ultrastructure)
• Protective Agents (pharmacology)
• RNA Interference
• Rats
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Transfection