Caveolin-3 Overexpression Attenuates Cardiac Hypertrophy via Inhibition of T-type Ca2+ Current Modulated by Protein Kinase Cα in Cardiomyocytes

J Biol Chem. 2015 Sep 4;290(36):22085-100. doi: 10.1074/jbc.M115.674945. Epub 2015 Jul 13.


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.

Keywords: angiotensin II; calcium channel; cardiac hypertrophy; cardiomyocyte; caveolin; protein kinase C (PKC).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin II / pharmacology
  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Calcium Channels, T-Type / metabolism*
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Cardiomegaly / physiopathology
  • Caveolae / metabolism
  • Caveolin 3 / genetics
  • Caveolin 3 / metabolism*
  • Cells, Cultured
  • Gene Expression
  • Male
  • Membrane Potentials / drug effects
  • Mice, Inbred C57BL
  • Microscopy, Electron, Transmission
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / physiology*
  • Myocytes, Cardiac / ultrastructure
  • Patch-Clamp Techniques
  • Protein Kinase C-alpha / genetics
  • Protein Kinase C-alpha / metabolism*
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction


  • Calcium Channels, T-Type
  • Caveolin 3
  • Angiotensin II
  • Protein Kinase C-alpha