Circulation Research. 2002;91:517-524
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
© 2002 American Heart Association, Inc.
Cellular Biology |
L-Type Ca2+ Channel Density and Regulation Are Altered in Failing Human Ventricular Myocytes and Recover After Support With Mechanical Assist Devices
From the Cardiovascular Research Group, Temple University School of Medicine, Philadelphia, Pa.
Correspondence to Dr Steven Houser, Cardiovascular Research Group, Temple University School of Medicine, 3400 North Broad St, Philadelphia, PA 19140. 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%) and LVAD- (70±15%) than in F- (51±8%) 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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