title: Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo.
abstract: Human response to isoproterenol induced cardiac injury was evaluated by gene and protein pathway changes in human heart slices, and compared to rat heart slices and rat heart in vivo. Isoproterenol (10 and 100μM) altered human and rat heart slice markers of oxidative stress (ATP and GSH) at 24h. In this in vivo rat study (0.5mg/kg), serum troponin concentrations increased with lesion severity, minimal to mild necrosis at 24 and 48h. In the rat and the human heart, isoproterenol altered pathways for apoptosis/necrosis, stress/energy, inflammation, and remodeling/fibrosis. The rat and human heart slices were in an apoptotic phase, while the in vivo rat heart exhibited necrosis histologically and further progression of tissue remodeling. In human heart slices genes for several heat shock 70kD members were altered, indicative of stress to mitigate apoptosis. The stress response included alterations in energy utilization, fatty acid processing, and the up-regulation of inducible nitric oxide synthase, a marker of increased oxidative stress in both species. Inflammation markers linked with remodeling included IL-1α, Il-1β, IL-6 and TNFα in both species. Tissue remodeling changes in both species included increases in the TIMP proteins, inhibitors of matrix degradation, the gene/protein of IL-4 linked with cardiac fibrosis, and the gene Ccl7 a chemokine that induces collagen synthesis, and Reg3b a growth factor for cardiac repair. This study demonstrates that the initial human heart slice response to isoproterenol cardiac injury results in apoptosis, stress/energy status, inflammation and tissue remodeling at concentrations similar to that in rat heart slices.
authors.affiliation: Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine, CA 92612, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Herrmann
authors.affiliation: Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine, CA 92612, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Heale
authors.affiliation: Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine, CA 92612, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Bieraugel
authors.affiliation: Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine, CA 92612, USA.
authors.forename: Meg
authors.initials: M
authors.lastname: Ramos
authors.affiliation: Vitron Inc., Tucson, AZ, USA.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Fisher
authors.affiliation: Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine, CA 92612, USA. Electronic address: vickers_alison@allergan.com.
authors.forename: Alison E M
authors.initials: AE
authors.lastname: Vickers
mesh_terms: D000368:Aged; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D054410:Chemokine CCL7 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000473:pathology / Q000628:therapy; D006321:Heart / Q000187:drug effects*; D006335:Heart Injuries / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000073718:Pancreatitis-Associated Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014336:Troponin / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D054410:Chemokine CCL7; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D015850:Interleukin-6; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; C560822:TIMP1 protein, human; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D014336:Troponin; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007545:Isoproterenol
keywords: Cardiac injury; Gene and protein pathways; Human heart slices; Isoproterenol; Rat heart in vivo; Rat heart slices