Post-transcriptional alterations in the expression of cardiac Na+ channel subunits in chronic heart failure

Clinical and experimental evidence has recently accumulated about the importance of alterations of Na+ channel (NaCh) function and slow myocardial conduction for arrhythmias in infarcted and failing hearts (i.e., heart failure, HF). The present study evaluated the molecular mechanisms of local alterations in the expression of NaCh subunits which underlie Na+ current (INa) density decrease in HF. HF was induced in five dogs by sequential coronary microembolization and developed approximately 3 months after the last embolization (left ventricle (LV), ejection fraction = 27 ± 7%). Five normal dogs served as a control group. Ventricular cardiomyocytes were isolated enzymatically from LV mid-myocardium and INa was measured by whole-cell patch-clamp. The mRNA encoding the cardiac-specific NaCh α-subunit Nav1.5, and one of its auxiliary subunits β1 (NaChβ1), were analyzed by competitive reverse transcription-polymerase chain reaction. Protein levels of Nav1.5, NaChβ1 and NaChβ2 were evaluated by western blotting. The maximum density of INa/Cm was decreased in HF (n = 5) compared to control hearts (33.2 ± 4.4 vs. 50.0 ± 4.9 pA/pF, mean ± S.E.M., n = 5, P < 0.05). The steady-state inactivation and activation of INa remained unchanged in HF compared to control hearts. The levels of mRNA encoding Nav1.5, and NaChβ1 were unaltered in FH. However, Nav1.5 protein expression was reduced about 30% in HF, while NaChβ1 and NaChβ2 protein were unchanged. We conclude that experimental HF in dogs results in post-transcriptional changes in cardiac NaCh α-subunit expression.