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Ca super(2+) Influx-Induced Sarcoplasmic Reticulum Ca super(2+) Overload Causes Mitochondrial-Dependent Apoptosis in Ventricular Myocytes

Increases in Ca super(2+) influx through the L-type Ca super(2+) channel (LTCC, Cav1.2) augment sarcoplasmic reticulum (SR) Ca super(2+) loading and the amplitude of the cytosolic Ca super(2+) transient to enhance cardiac myocyte contractility. Our hypothesis is that persistent increases in Ca super...

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Published in:Circulation research 2005-11, Vol.97 (10), p.1009-1017
Main Authors: Chen, Xiongwen, Zhang, Xiaoying, Kubo, Hajime, Harris, David M, Mills, Geoffrey D, Moyer, Jed, Berretta, Remus, Potts, Sabine Telemaque, Marsh, James D, Houser, Steven R
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Language:English
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Summary:Increases in Ca super(2+) influx through the L-type Ca super(2+) channel (LTCC, Cav1.2) augment sarcoplasmic reticulum (SR) Ca super(2+) loading and the amplitude of the cytosolic Ca super(2+) transient to enhance cardiac myocyte contractility. Our hypothesis is that persistent increases in Ca super(2+) influx through the LTCC cause apoptosis if the excessive influx results in SR Ca super(2+) overload. Feline ventricular myocytes (VMs) in primary culture were infected with either an adenovirus (Ad) containing a rat Cav1.2 {szligbeta} sub(2a) subunit-green fluorescent protein (GFP) fusion gene (Ad{szligbeta} sub(2a)) to increase Ca super(2+) influx or with AdGFP as a control. Significantly fewer {szligbeta} sub(2a)-VMs (21.4 plus or minus 5.6%) than GFP-VMs (99.6 plus or minus 1.7%) were viable at 96 hours. A fraction of {szligbeta} sub(2a)-VMs (20.8 plus or minus 1.8%) contracted spontaneously (SC-{szligbeta} sub(2a)-VMs), and viability was significantly correlated with the percentage of SC-{szligbeta} sub(2a)-VMs. Higher percentages of apoptotic nuclei, DNA laddering, and cytochrome C release were detected in {szligbeta} sub(2a)-VMs. This apoptosis was prevented with pancaspase or caspase-3 or caspase-9 inhibitors. L-type calcium current (I sub(Ca-L)) density was greater in {szligbeta} sub(2a)-VMs (23.4 plus or minus 2.8 pA/pF) than in GFP-VMs (7.6 plus or minus 1.6 pA/pF). SC-{szligbeta} sub(2a)-VMs had higher diastolic intracellular Ca super(2+) (Indo-1 ratio: 1.1 plus or minus 0.1 versus 0.7 plus or minus 0.03, P
ISSN:0009-7330
1524-4571