title: Caveolin-3 Overexpression Attenuates Cardiac Hypertrophy via Inhibition of T-type Ca2+ Current Modulated by Protein Kinase Cα in Cardiomyocytes.
abstract: Pathological cardiac hypertrophy is characterized by subcellular remodeling of the ventricular myocyte with a reduction in the scaffolding protein caveolin-3 (Cav-3), altered Ca(2+) cycling, increased protein kinase C expression, and hyperactivation of calcineurin/nuclear factor of activated T cell (NFAT) signaling. However, the precise role of Cav-3 in the regulation of local Ca(2+) signaling in pathological cardiac hypertrophy is unclear. We used cardiac-specific Cav-3-overexpressing mice and in vivo and in vitro cardiac hypertrophy models to determine the essential requirement for Cav-3 expression in protection against pharmacologically and pressure overload-induced cardiac hypertrophy. Transverse aortic constriction and angiotensin-II (Ang-II) infusion in wild type (WT) mice resulted in cardiac hypertrophy characterized by significant reduction in fractional shortening, ejection fraction, and a reduced expression of Cav-3. In addition, association of PKCα and angiotensin-II receptor, type 1, with Cav-3 was disrupted in the hypertrophic ventricular myocytes. Whole cell patch clamp analysis demonstrated increased expression of T-type Ca(2+) current (ICa, T) in hypertrophic ventricular myocytes. In contrast, the Cav-3-overexpressing mice demonstrated protection from transverse aortic constriction or Ang-II-induced pathological hypertrophy with inhibition of ICa, T and intact Cav-3-associated macromolecular signaling complexes. siRNA-mediated knockdown of Cav-3 in the neonatal cardiomyocytes resulted in enhanced Ang-II stimulation of ICa, T mediated by PKCα, which caused nuclear translocation of NFAT. Overexpression of Cav-3 in neonatal myocytes prevented a PKCα-mediated increase in ICa, T and nuclear translocation of NFAT. In conclusion, we show that stable Cav-3 expression is essential for protecting the signaling mechanisms in pharmacologically and pressure overload-induced cardiac hypertrophy.
authors.affiliation: From the Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Yogananda S
authors.initials: YS
authors.lastname: Markandeya
authors.affiliation: From the Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Phelan
authors.affiliation: From the Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Marites T
authors.initials: MT
authors.lastname: Woon
authors.affiliation: From the Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Keefe
authors.affiliation: From the Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Courtney R
authors.initials: CR
authors.lastname: Reynolds
authors.affiliation: From the Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: August
authors.affiliation: From the Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.affiliation: the Veterans Affairs San Diego Healthcare Systems, San Diego, California 92161, and the Department of Anesthesiology, University of California at San Diego, La Jolla, California 92161.
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.affiliation: the Veterans Affairs San Diego Healthcare Systems, San Diego, California 92161, and the Department of Anesthesiology, University of California at San Diego, La Jolla, California 92161.
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.affiliation: From the Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53706, rcb@medicine.wisc.edu.
authors.forename: Ravi C
authors.initials: RC
authors.lastname: Balijepalli
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D021941:Caveolae / Q000378:metabolism; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015870:Gene Expression; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020747:Calcium Channels, T-Type; D051244:Caveolin 3; D000804:Angiotensin II; D051571:Protein Kinase C-alpha
keywords: angiotensin II; calcium channel; cardiac hypertrophy; cardiomyocyte; caveolin; protein kinase C (PKC)