The Role of KCNE2 in Cardiac Hypertrophy and Heart Failure

• Applicant: Privatdozent Dr. Torsten Roepke
• Subject Area: Cardiology, Angiology
• Term: from 2012 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 216815780

Downregulation of cardiac K+ currents has been described in hypertrophic heart disease and heart failure. However, so far no mutations in potassium channels genes have been described in patients with cardiac hypertrophy and heart failure. It therefore remains controversial whether K+ current down regulation represents a primary cause of cardiac hypertrophy/heart failure or epiphenomena. KCNE2 is a voltage gated potassium channel ancillary subunit that is associated with inherited and acquired long QT syndrome. We recently developed KCNE2-/- mice. KCNE2-/- mice have normal cardiac morphology and function at 3-6 months of age despite a prolonged repolarization. However, aged KCNE2-/- mice develop 2 significant cardiac hypertrophy and severe heart failure. Furthermore, after Ang. II stimulation 3-6 months old KCNE2-/- mice demonstrate significant hypertrophy and fibrosis compared to age-matched wild type siblings. Preliminary data also indicate alterations in calcium handling proteins (Phospholamban and NCX) and regulation of Calcium currents (ICa) in hypertrophied failing KCNE2-/- hearts. We therefore intend to further characterize the hypertrophy/heart failure phenotype in our KCNE2-/- mouse model. We intend to further elucidate the specific signalling pathway (s) in this model that lead (s) to hypertrophy and subsequent heart failure with an emphasis on the Calcium dependent Calcineurin/NFAT and PKD/CaMK pathway. Furthermore, to rule out extra cardiac effects on the hypertrophy/heart failure phenotype we will generate a cardiac specific KCNE2-/- gene knockout.

• DFG Programme: Research Grants