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: Julia E Herrmann, Jason Heale, Mike Bieraugel, Meg Ramos, Robyn L Fisher, Alison E M Vickers
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 274 Issue 2 Pg. 302-12 (Jan 15 2014) ISSN: 1096-0333 [Electronic] United States
• PMID: 24286936 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Neoplasm
• Biomarkers, Tumor
• Chemokine CCL7
• Interleukin-1alpha
• Interleukin-1beta
• Interleukin-6
• Lectins, C-Type
• Pancreatitis-Associated Proteins
• REG3A protein, human
• TIMP1 protein, human
• TIMP1 protein, rat
• Tissue Inhibitor of Metalloproteinase-1
• Troponin
• Tumor Necrosis Factor-alpha
• Interleukin-4
• NOS2 protein, human
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Isoproterenol

Topics

• Aged
• Animals
• Antigens, Neoplasm (genetics, metabolism)
• Apoptosis (drug effects)
• Biomarkers, Tumor (genetics, metabolism)
• Chemokine CCL7 (genetics, metabolism)
• Female
• Fibrosis (pathology, therapy)
• Heart (drug effects)
• Heart Injuries (chemically induced, pathology)
• Humans
• In Vitro Techniques
• Interleukin-1alpha (genetics, metabolism)
• Interleukin-1beta (genetics, metabolism)
• Interleukin-4 (genetics, metabolism)
• Interleukin-6 (genetics, metabolism)
• Isoproterenol (pharmacology)
• Lectins, C-Type (genetics, metabolism)
• Male
• Middle Aged
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Oxidative Stress (drug effects)
• Pancreatitis-Associated Proteins
• Rats
• Rats, Sprague-Dawley
• Tissue Inhibitor of Metalloproteinase-1 (genetics, metabolism)
• Troponin (blood)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Up-Regulation
• Young Adult