Heart failure is associated with dysregulation of intracellular calcium ([Ca2+]i), reduction in myofibrils, and increased activation of Ras, a regulator of signal-transduction pathways. To evaluate the potential effects of Ras on [Ca2+]i, we expressed constitutively active Ras (Ha-RasV12) in cardiac myocytes and monitored [Ca2+]i via fluorescence and electrophysiological techniques. Ha-RasV12 reduced the magnitude of the contractile calcium transients. Unexpectedly, however, calcium loading of the sarcoplasmic reticulum was increased, suggesting that Ha-RasV12 introduces a defect in excitation-calcium release coupling. Consistent with this idea, L-channel calcium currents were reduced by Ha-RasV12, which also downregulated the activity of the L-channel gene promoter. Coexpression of L-channels and SERCA2 largely corrected Ha-RasV12-induced dysregulation of [Ca2+]i. Furthermore, whereas Ha-RasV12 downregulated myofibrils, this effect was blocked by coexpression of L-channels. These results suggest that Ras downregulates L-channel expression, which may play a pathophysiological role in cardiac disease.
- Cardiac hypertrophy
- L-type calcium channel
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine