Key result
Caveolin-3 overexpression protected against pharmacologically and pressure overload-induced cardiac hypertrophy by inhibiting T-type Ca2+ current modulated by PKCα.
Stable Caveolin-3 expression protects against cardiac hypertrophy by inhibiting PKCα-modulated T-type Ca2+ currents and NFAT signaling in preclinical models.
Hypothesis-generating for caveolin-3 in hypertrophy models; clinical translation untested.
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.
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Markandeya et al. (2015) studied Cardiac hypertrophy. Caveolin-3 overexpression vs. Wild type (WT) mice was evaluated on Cardiac hypertrophy and T-type Ca2+ current (ICa, T). Caveolin-3 overexpression protected against pharmacologically and pressure overload-induced cardiac hypertrophy by inhibiting T-type Ca2+ current modulated by PKCα.
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