Chronic beta-adrenoreceptor stimulation in vivo decreased Bcl-2 and increased Bax expression but did not activate apoptotic pathways in mouse heart.
Prolonged activation of the sympathetic nervous system is deleterious to heart function. In vitro beta1-adrenergic activation promotes apoptosis, whereas beta2-adrenergic activation reduces apoptosis in cultured adult cardiomyocytes. To determine the effect of chronic catecholamine infusion in vivo, we measured apoptosis marker expression in C57Bl/6 and catecholamine-sensitive Egr-1 deficient mice after treatment with the nonspecific beta-adrenergic agonist, isoproterenol, the beta1-specific agonist, dobutamine, or the beta2-specific agonist, metaproterenol. Antiapoptotic and proapoptotic protein expression, cytochrome c release and caspases 3, 9, and 12 activation products were measured on immunoblots. Catecholamine-treated mice had decreased Bcl-2 and increased Bax and BNIP1 expression, suggesting mitochondria-dependent apoptosis pathway activation. However, cytosolic cytochrome c or caspase 3 or 9 activation products were not detected. In mice, increased molecular chaperone expression and caspase 12 activation characterize endoplasmic-reticulum-driven apoptosis. Clusterin expression was increased in catecholamine-treated mice, but GRP78 expression was not increased, and caspase 12 activation products were not detected. Thus, neither the mitochondrial nor the endoplasmic apoptotic pathway was fully activated. Further, Egr-1 deficiency did not increase cardiac apoptosis. We conclude that although chronic in vivo infusion of beta1- or beta2-adrenergic receptor agonists partially activates the apoptosis program, full activation of the caspase cascade requires more, or other, cardiac insults.
Dostanic
Stevan
S
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis--Jewish General Hospital, Montréal, QC, Canada.
Servant
Nicolas
N
Wang
Chunlei
C
Chalifour
Lorraine E
LE
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001835:Body Weight / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D051152:Clusterin; D004268:DNA-Binding Proteins / Q000172:deficiency; D004280:Dobutamine / Q000008:administration & dosage / Q000493:pharmacokinetics; D004359:Drug Therapy, Combination; D051766:Early Growth Response Protein 1; D000091342:Endoplasmic Reticulum Chaperone BiP; D015870:Gene Expression / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects / Q000235:genetics*; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D017874:Immediate-Early Proteins / Q000172:deficiency; D007260:Infusion Pumps; D007545:Isoproterenol / Q000008:administration & dosage / Q000493:pharmacokinetics; D009921:Metaproterenol / Q000008:administration & dosage / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010656:Phenylephrine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects* / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency; D051028:bcl-2-Associated X Protein
D000318:Adrenergic beta-Agonists; C494827:Bax protein, mouse; C495243:Clu protein, mouse; D051152:Clusterin; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006023:Glycoproteins; C000717248:Hspa5 protein, mouse; D017874:Immediate-Early Proteins; D018832:Molecular Chaperones; D019253:Proto-Oncogene Proteins c-bcl-2; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D010656:Phenylephrine; D004280:Dobutamine; D009921:Metaproterenol; D012313:RNA; D007545:Isoproterenol