title: Caveolin-3 plays a critical role in autophagy after ischemia-reperfusion.
abstract: Autophagy is a dynamic recycling process responsible for the breakdown of misfolded proteins and damaged organelles, providing nutrients and energy for cellular renovation and homeostasis. Loss of autophagy is associated with cardiovascular diseases. Caveolin-3 (Cav-3), a muscle-specific isoform, is a structural protein within caveolae and is critical to stress adaptation in the heart. Whether Cav-3 plays a role in regulating autophagy to modulate cardiac stress responses remains unknown. In the present study, we used HL-1 cells, a cardiac muscle cell line, with stable Cav-3 knockdown (Cav-3 KD) and Cav-3 overexpression (Cav-3 OE) to study the impact of Cav-3 in regulation of autophagy. We show that traditional stimulators of autophagy (i.e., rapamycin and starvation) result in upregulation of the process in Cav-3 OE cells while Cav-3 KD cells have a blunted response. Cav-3 coimmunoprecipitated with beclin-1 and Atg12, showing an interaction of caveolin with autophagy-related proteins. In the heart, autophagy may be a major regulator of protection from ischemic stress. We found that Cav-3 KD cells have a decreased expression of autophagy markers [beclin-1, light chain (LC3-II)] after simulated ischemia and ischemia-reperfusion (I/R) compared with WT, whereas OE cells showed increased expression. Moreover, Cav-3 KD cells showed increased cell death and higher level of apoptotic proteins (cleaved caspase-3 and cytochrome c) with suppressed mitochondrial function in response to simulated ischemia and I/R, whereas Cav-3 OE cells were protected and had preserved mitochondrial function. Taken together, these results indicate that autophagy regulates adaptation to cardiac stress in a Cav-3-dependent manner.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California.|Sam and Rose Stein Institute for Research on Aging, Department of Psychiatry, School of Medicine, University of California, San Diego, California.|Veterans Affairs San Diego Healthcare System, San Diego, California; and.
authors.forename: Adam
authors.initials: A
authors.lastname: Kassan
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California.|Veterans Affairs San Diego Healthcare System, San Diego, California; and.
authors.forename: Uyen
authors.initials: U
authors.lastname: Pham
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California.|Veterans Affairs San Diego Healthcare System, San Diego, California; and.
authors.forename: Quynhmy
authors.initials: Q
authors.lastname: Nguyen
authors.affiliation: School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Reichelt
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California.|Veterans Affairs San Diego Healthcare System, San Diego, California; and.
authors.forename: Eunbyul
authors.initials: E
authors.lastname: Cho
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California.|Veterans Affairs San Diego Healthcare System, San Diego, California; and.
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Patel
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California.|Veterans Affairs San Diego Healthcare System, San Diego, California; and.
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California.|Veterans Affairs San Diego Healthcare System, San Diego, California; and.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California; hepatel@ucsd.edu.|Veterans Affairs San Diego Healthcare System, San Diego, California; and.
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D021941:Caveolae / Q000378:metabolism; D051244:Caveolin 3 / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D006321:Heart / Q000502:physiology; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D015424:Reperfusion / Q000379:methods
chemical_list: D051017:Apoptosis Regulatory Proteins; D051244:Caveolin 3; D045304:Cytochromes c; D053148:Caspase 3
keywords: mitochondria