Circulation Research. 2002
Published online before print August 15, 2002, doi: 10.1161/01.RES.0000033988.13062.7C
Published online before print August 15, 2002, doi: 10.1161/01.RES.0000033988.13062.7C
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Submitted on April 18, 2002
Revised on August 7, 2002
Accepted on August 7, 2002
L-Type Ca2+ Channel Density and Regulation Are Altered in Failing Human Ventricular Myocytes and Recover After Support With Mechanical Assist Devices
Xiongwen Chen ;
From the Cardiovascular Research Group, Temple University School of Medicine, Philadelphia, Pa.
* To whom correspondence should be addressed. E-mail: srhouser{at}unix.temple.edu.
Ca2+ influx through the L-type calcium channel (LTCC) induces Ca2+ release from the sarcoplasmic reticulum (SR) and maintains SR Ca2+ loading. Alterations in LTCC properties, their contribution to the blunted adrenergic responsiveness in failing hearts and their recovery after support with LV assist devices (LVAD) were studied. L-type Ca2+ current (ICa,L) was measured under basal conditions and in the presence of isoproterenol (ISO), dibutyryl-cAMP (db-cAMP), Bay K 8644 (BayK), Okadaic acid (OA, a phosphatase inhibitor), and phosphatase 2A (PP2A) in nonfailing (NF), failing (F), and LVAD-supported human left ventricular myocytes (HVMs). Basal ICa,L density was not different in the 3 groups but ICa,L was activated at more negative voltages in F- and LVAD- versus NF-HVMs (V0.5: -7.18±1.4 and -7.0±0.9 versus 0.46±1.1 mV). Both ISO and db-cAMP increased ICa,L in NF- and LVAD- significantly more than in F-HVMs (NF >LVAD> F: ISO: 90±15% versus 77±19% versus 24±12%; db-cAMP: 235%>172%>90%). ISO caused a significant leftward shift of the ICa,L activation curve in NF- and LVAD- but not in F-HVMs. After ISO and db-cAMP, the ICa,L activation was not significantly different between groups. BayK also increased ICa,L more in NF- (81±30.25) and LVAD- (70±15.25) than in F- (51±8.25) HVMs. OA increased ICa,L by 85.6% in NF-HVMs but had no effect in F-HVMs, while PP2A decreased ICa,L in F-HVMs by 35% but had no effect in NF-HVMs. These results suggest that the density of LTCC is reduced in F-HVMs but basal ICa,L density is maintained by increasing in LTCC phosphorylation.
Key words: L-type calcium channel • heart failure • left ventricle assist device • PKA-dependent phosphorylation
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