Abstract 19124: Ca Overload Induced Pathological Cardiac Remodeling Rescued by Na-ca Exchanger Overexpression
Aims: Sarcoplasmic reticulum (SR) Ca2+ overload plays an essential role in pathological cardiac remodeling including hypertrophy, cell death, fibrosis and arrhythmias. Normalization of SR Ca2+ load holds a great promise for the prevention and treatment of heart failure. Here we test this hypothesis by determining if normalization of Ca2+ overload with Na-Ca exchange overexpression in the murine hearts or cultured feline myocytes overexpressing Cav1.2β2a subunit rescues the adverse remodeling and cell death.
Results: 1. In vivo, overexpression of β2a for 4 months induced cardiac hypertrophy (HW/BW, Control: 4.16±0.1mg/g, β2a: 4.64±0.24mg/g) accompanied by cell death and fibrosis while these parameters were largely normalized in NCX-coexpression mice (HW/BW, β2a-ncx: 4.24±0.11mg/g). 2. The structural remodeling was supported by ECHO data showing less increases in left ventricular posterior wall and interventricular septal wall thickness and better preserved cardiac function (fractional shortening: β2a: 30.5±9.8%; β2a-ncx: 48.1±7.85); 3. Patch-clamp studies revealed that β2a transgenic myocytes had larger Ca2+ currents (Control: -12.7±2.1 pA/pF; β2a: -17.3±3.4 pA/pF) and co-expression of NCX did not normalize the increased Ica (β2a-ncx: -15.7±1.5 pA/pF). 4. Overexpressing Cav1.2β2a in cultured feline ventricular myocytes increased ICa significantly (control:-2.1±0.3 pA/pF, β2a:-19.4±5.9 pA/pF, β2a-NCX:-16.4±2.3 pA/pF). 5. Overexpression of β2a in feline cells for 48 h resulted in prominent SR Ca2+ overload (caffeine induced Ca2+ transient peak by Fluo-4: F/F0, control:3.2±1.0, β2a:4.8±1.2) while co-expression of NCX prevented it (β2a-NCX: 3.4±1.3). 6. Prominent cell death was also confirmed in β2a-overexpressing feline myocytes (survival rate: Control: 69.9±9.5%, β2a:26.2±6.4%) and cell death was partially protected by the coexpression of NCX (β2a-ncx: 44.6±5.7%).
Conclusion: Over-expression of NCX is sufficient for blocking pathological cardiac remodeling as induced by SR Ca2+ overload and may represent a novel therapeutic strategy for heart failure.
- © 2013 by American Heart Association, Inc.