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 (I(Na)) 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 I(Na) was measured by whole-cell patch-clamp. The mRNA encoding the cardiac-specific NaCh alpha-subunit Na(v)1.5, and one of its auxiliary subunits beta 1 (NaCh beta 1), were analyzed by competitive reverse transcription-polymerase chain reaction. Protein levels of Na(v)1.5, NaCh beta 1 and NaCh beta 2 were evaluated by western blotting. The maximum density of I(Na)/C(m) 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 I(Na) remained unchanged in HF compared to control hearts. The levels of mRNA encoding Na(v)1.5, and NaCh beta 1 were unaltered in FH. However, Na(v)1.5 protein expression was reduced about 30% in HF, while NaCh beta 1 and NaCh beta 2 protein were unchanged. We conclude that experimental HF in dogs results in post-transcriptional changes in cardiac NaCh alpha-subunit expression.
Zicha
Stephen
S
Department of Medicine and Research Center, Montreal Heart Institute and University of Montreal, Quebec, Canada.
Maltsev
Victor A
VA
Nattel
Stanley
S
Sabbah
Hani N
HN
Undrovinas
Albertas I
AI
D000818:Animals; D001145:Arrhythmias, Cardiac; D015153:Blotting, Western; D017931:DNA Primers / Q000737:chemistry; D004285:Dogs; D004594:Electrophysiology; D006333:Heart Failure / Q000235:genetics*; D006352:Heart Ventricles / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D062548:Voltage-Gated Sodium Channel beta-2 Subunit
D017931:DNA Primers; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; C117620:SCN2B protein, human; C568320:SCN5A protein, human; D015222:Sodium Channels; D062548:Voltage-Gated Sodium Channel beta-2 Subunit