Abstract 447: Targeted Overexpression of L-type Calcium Channel Beta2a Subunit Regulates Cardiac Hypertrophy and Death after Stress Stimulation
[Introduction] Calcium influx through the L-type calcium channel (LTCC) triggers excitation-contraction coupling, although it may also influence cardiac hypertrophy and heart failure through calcium-sensitive signaling pathways. The LTCC is comprised of 3 subunits (α, β and α2/δ), where the β2 subunit enhances activity of the pore forming α subunit.
[Objective and Methods] Here we specifically enhanced calcium influx through the LTCC by regulated β2a overexpression in the heart using a tetracycline-inducible (tTA) bi-transgenic (tg) system in the mouse.
[Results] Three β2a responder lines were obtained and crossed with tTA expressing mice to generate double transgenics (DTG). The maximum LTCC current (ICa-L) density was significantly higher (p<0.01) in isolated adult cardiomyocyte from DTG, (24.3±2.6pA/pF) compared with non-tg littermate controls (NLC) (13.7±0.7pA/pF). Consistent with this observation, young DTG mice showed enhanced systolic function, yet as these mice aged they showed atrial enlargement, increased heart-weight to body-weight (HW/BW;mg/g) ratio (9.1±1.5, n=9 vs 5.2±0.3, n=7; p<0.05) and decreased fractional shortening (FS) (26.0±1.1%n=9 vs 44.7±1.5% n=7, p<0.01). Pressure overload stimulation enhanced HW/BW in young DTG mice more than in NLC mice (9.1±0.6, n=8 vs 6.9±0.3 n=10, p<0.01) and lead to greater decreases in FS (33.8±1.5% vs 42.9±1.5%, p<0.05). Isoproterenol infusion dramatically enhanced mortality in DTG mice compared with NLC mice (6/10 vs 0/10), decreased function in the surviving animals, and induced massive cell death in the ventricles.
[Conclusion] Increased expression of the LTCC β2a subunit in the heart enhances cardiac hypertrophy/pathology and suggests that enhanced sarcolemmal calcium influx can be pathological by promoting cardiac cell death.