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.
Highlights
Exacerbated tissue and organ damage produced by the restoration of blood flow after ischemia is known as ischemia/reperfusion (I/R) injury
Since lactate dehydrogenase (LDH) leakage is widely used as a marker of cellular damage, cardiomyocyte cells injury was assessed by determining LDH activity in culture medium at the end of reoxygenation
These findings indicated that N-n-butyl haloperidol iodide H/R (F2) could promote cell survival and reduce cell damage in H9c2 cells subjected to H/R
Summary
Exacerbated tissue and organ damage produced by the restoration of blood flow after ischemia is known as ischemia/reperfusion (I/R) injury. Many studies report that autophagy plays a key role in myocardial I/R injury in both animal models and cellular models by causing progressive degeneration of the heart [1]. Autophagy is a dynamic process that turns over organelles and proteins through a lysosome-associated degradation process, and serves a critical function in cellular homoeostasis by regulating cell survival and cell death pathways [2]. The role of autophagy in contributing to cell survival and death in the heart remains controversial [3, 4]. Several lines of evidence suggest that autophagy may promote cell survival by purging the cell of damaged proteins to generate the intracellular building blocks required to maintain vital functions during nutrientlimiting conditions, such as ischemia or hypoxia [5, 6]. Inhibition of autophagy reduces the size of myocardial infarction and cardiac myocyte apoptosis in beclin 1+/− mice [4]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
