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 | Yogananda S Markandeya, Laura J Phelan, Marites T Woon, Alexis M Keefe, Courtney R Reynolds, Benjamin K August, Timothy A Hacker, David M Roth, Hemal H Patel, Ravi C Balijepalli |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 290
Issue 36
Pg. 22085-100
(Sep 04 2015)
ISSN: 1083-351X [Electronic] United States |
PMID | 26170457
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
|
Copyright | © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. |
Chemical References |
- Calcium Channels, T-Type
- Caveolin 3
- Angiotensin II
- Protein Kinase C-alpha
|
Topics |
- Angiotensin II
(pharmacology)
- Animals
- Animals, Newborn
- Blotting, Western
- Calcium Channels, T-Type
(metabolism)
- Cardiomegaly
(genetics, metabolism, physiopathology)
- Caveolae
(metabolism)
- Caveolin 3
(genetics, metabolism)
- Cells, Cultured
- Gene Expression
- Male
- Membrane Potentials
(drug effects)
- Mice, Inbred C57BL
- Microscopy, Electron, Transmission
- Myocytes, Cardiac
(metabolism, physiology, ultrastructure)
- Patch-Clamp Techniques
- Protein Kinase C-alpha
(genetics, metabolism)
- RNA Interference
- Reverse Transcriptase Polymerase Chain Reaction
|