KChIP2 Attenuates Cardiac Hypertrophy through Regulation of Ito

Background: Recent evidence shows that the auxiliary subunit KChIP2 represents a new potential regulator of Ito density. KChIP2 expression has been found to be significantly decreased in hypertrophy and heart failure. Our aim was to examine the role of KChIP2 in the regulation of hypertrophic pathways and induction of cardiac hypertrophy and failure. Methods/results: We studied cultured cardiomyocytes and rat hearts subjected to aortic banding (AB) infected with an adenovirus carrying either the KChIP2 gene (Ad.KChIP2) or the β-galactosidase gene (Ad.β-gal). KChIP2 overexpression in neonatal cardiomyocytes resulted in a significant increase in Kv4.2 and Kv4.3 proteins, suggesting that KChIP2 may facilitate the trafficking of these proteins to the cell surface. Echocardiography, performed 8–10 days post banding and viral infection, showed that banded hearts transduced with Ad.KChIP2 demonstrated significant decreases in interventricular septal (IVS) thicknesses (IVSd 0.26±0.03 cm; IVSs 0.37±0.05 cm, n=10) as well as left ventricular posterior wall (LVPW) thicknesses (LVPWd 0.27±0.02 cm; LVPWs 0.34±0.03 cm, n=10) compared to Ad.β-gal (IVSd 0.31±0.03 cm; IVSs 0.44±0.03 cm, n=6; P<0.04 and LVPWd 0.37±0.01 cm; LVPWs 0.38±0.04 cm, n=6, respectively). Ito density was decreased in myocytes isolated from banded hearts infected with Ad.β-gal (10.9±1.0 pA/pF n=11) compared to myocytes derived from sham hearts (25.6±0.40 pA/pF n=14, P<0.05 at +60 mV). Overexpression of KChIP2 significantly increased Ito densities (32.3±0.9 pA/pF, n=12) and remarkably shortened the APD at 90% (10.2±2.4 ms, n=10) compared to AB myocytes infected with Ad.β-gal (58.9±4.2 ms, n=20 P<0.05). These data demonstrate that KChIP2 gene transfer can specifically shorten APD and increase the expression of Kv4.2/3-based Ito which mirrors the increase in Ito density. Mechanical properties of myocytes isolated from aortic banded hearts infected with Ad.β-gal were associated with increased peak calcium and cell shortening when compared with Sham. However, overexpression of KChIP2 attenuated the enhanced contractile function seen in Ad.β-gal hearts. These electrical and hypertrophic changes produced by KChIP2 were also paralleled by blockade of protein synthesis and MAP kinases activation following angiotensin II-induced hypertrophy response in cultured neonatal myocytes. Conclusion: Taken together, these data suggest that overexpression of KChIP2 can attenuate the development of cardiac hypertrophy possibly through restoration of Ito densities and modulation of MAPK pathway.