Expression of the cytoplasmic domain of beta1 integrin induces apoptosis in adult rat ventricular myocytes (ARVM) via the involvement of caspase-8 and mitochondrial death pathway.
Stimulation of beta-adrenergic receptor (beta-AR) induces cardiac myocyte apoptosis. Integrins, a family of cell-surface receptors, play an important role in the regulation of cardiac myocyte apoptosis and ventricular remodeling. Cleavage of extracellular domain of beta1 integrin, also called integrin shedding, is observed during cardiac hypertrophy and progression to early heart failure. Here we show that stimulation of beta-AR induces beta1 integrin fragmentation in mouse heart. To examine the role of intracellular domain of beta1 integrin in cardiac myocyte apoptosis, a chimeric receptor consisting of the cytoplasmic tail domain of beta(1A) integrin and the extracellular/transmembrane domain of the interleukin-2 receptor (TAC-beta1) was expressed in adult rat ventricular myocytes (ARVM) using adenoviruses. TAC-beta1 increased the percentage of apoptotic ARVM as measured by TUNEL-staining assay. TAC-beta1-induced apoptosis was found to be associated with increased cytosolic cytochrome c and decreased mitochondrial membrane potential. TAC-beta1 increased caspase-8 activity. Z-IETD-FMK, a specific caspase-8 inhibitor, significantly inhibited TAC-beta1-induced apoptosis. TAC-beta1 expression also increased cleavage of Bid, a pro-apoptotic Bcl-2 family protein. These data suggest that shedding of beta1 integrin may be a mechanism of induction of apoptosis during beta-AR-stimulated cardiac remodeling.
Menon
Bindu
B
Department of Physiology, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, PO Box 70576, Johnson City, TN 37614, USA.
Krishnamurthy
Prasanna
P
Kaverina
Ekaterina
E
Johnson
Jennifer N
JN
Ross
Robert S
RS
Singh
Mahipal
M
Singh
Krishna
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000502:physiology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008929:Mitochondria, Heart / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000502:physiology
D051023:BH3 Interacting Domain Death Agonist Protein; C494816:Bid protein, rat; D019012:Integrin beta1; D011943:Receptors, Adrenergic, beta; D015375:Receptors, Interleukin-2; D045304:Cytochromes c; D053181:Caspase 8