Abstract 17523: Cardiac Hypertrophy, Heart Failure and Altered Calcium Handling in Aged Kcne2-/- Mice
Down regulation of cardiac K+ currents has been described in hypertrophic heart disease and heart failure. However, so far no mutations in potassium channel genes have been found in patients that are associated with cardiac hypertrophy/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 repolarization defect caused by disruption of IKslow,1 and Ito,f. However, aged KCNE2-/- mice (12 months and older) develop significant cardiac hypertrophy and severe heart failure assessed by echocardiography and histology. Furthermore, after Angiotensin II and isoprenaline stimulation 3-6 months old KCNE2-/- mice also demonstrate significant hypertrophy and fibrosis compared to age-matched KCNE2+/+ siblings. Taqman PCR revealed molecular remodelling in hypertrophied failing KCNE2-/- hearts with induction of the fetal gene program (ANF re-expression), significant up regulation of Sodium-Calcium Exchanger (NCX) and significant down regulation of phospholamban. Alterations were also recapitulated on the protein level by Western Blotting. IonOptix® measurements revealed impaired cellular shortening and significantly prolonged cellular relaxation times, the systolic intracellular Ca2+ levels are increased in cardiomyocytes from old KCNE2-/- animals. The activity of the calcium dependent serin-threonin phophatase calcineurin is higher, MCIP mRNA significantly upregulated in 3-6 months old KCNE2-/- mice compared to age-matched KCNE2+/+ siblings. In whole-cell patch clamp recordings we found altered inactivation kinetics of the L-type Ca2+ channel and a blunted isoproterenol response in hypertrophied failing KCNE2-/- cardiomyocytes. We therefore conclude that primary disruption of repolarizing Kv currents by KCNE2 deletion leads to altered Calcium handling and consecutive induction of cardiac hypertrophy and heart failure.
- © 2012 by American Heart Association, Inc.