Age-associated impairment in TNF-alpha cardioprotection from myocardial infarction
| Autor: | Jingang Zheng, Munira Xaymardan, Jacquelyne M. Holm, Jorge R. Kizer, Dongqing Cai, Jay M. Edelberg |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Senescence
medicine.medical_specialty Pathology Aging Physiology medicine.medical_treatment Becaplermin Myocardial Infarction Receptors Tumor Necrosis Factor Mice Antigens CD Peptide Library Physiology (medical) Internal medicine medicine Animals Myocardial infarction Cardioprotection Platelet-Derived Growth Factor biology business.industry Tumor Necrosis Factor-alpha Growth factor Myocardium Proto-Oncogene Proteins c-sis medicine.disease Endothelial stem cell Mice Inbred C57BL Endocrinology Cytokine Receptors Tumor Necrosis Factor Type I Circulatory system biology.protein Cardiology and Cardiovascular Medicine business Platelet-derived growth factor receptor |
| Zdroj: | American journal of physiology. Heart and circulatory physiology. 285(2) |
| ISSN: | 0363-6135 |
| Popis: | Age-associated dysfunction in cardiac microvascular endothelial cells with impaired induction of cardioprotective platelet-derived growth factor (PDGF)-dependent pathways suggests that alterations in critical vascular receptor(s) may contribute to the increased severity of cardiovascular pathology in older persons. In vivo murine phage-display peptide library biopanning revealed a senescent decrease in cardiac microvascular binding of phage epitopes homologous to tumor necrosis factor-alpha (TNF-alpha), suggesting that its receptor(s) may be downregulated in older cardiac endothelial cells. Immunostaining demonstrated that TNF-receptor 1 (TNF-R1) density was significantly lower in the subendocardial endothelium of the aging murine heart. Functional studies confirmed the senescent dysregulation of TNF-alpha receptor pathways, demonstrating that TNF-alpha induced PDGF-B expression in cardiac microvascular endothelial cells of 4-mo-old, but not 24-mo-old, rats. Moreover, TNF-alpha mediated cardioprotective pathways were impaired in the aging heart. In young rat hearts, injection of TNF-alpha significantly reduced the extent of myocardial injury after coronary ligation: TNF-alpha, 7.9 +/- 1.9% left ventricular injury (n = 4) versus PBS, 16.2 +/- 7.9% (n = 10; P0.05). The addition of PDGF-AB did not augment the cardioprotective action of TNF-alpha. In myocardial infarctions of older hearts, however, TNF-alpha induced significant postcoronary occlusion mortality (TNF-alpha 80% vs. PBS 0%; n = 10 each, P0.05) that was reversed by the coadministration of PDGF-AB. Overall, these studies demonstrate that aging-associated alterations in TNF-alpha receptor cardiac microvascular pathways may contribute to the increased cardiovasular pathology of the aging heart. Strategies targeted at restoring TNF-alpha receptor-mediated expression of PDGF-B may improve cardiac microvascular function and provide novel approaches for treatment and possible prevention of cardiovascular disease in older individuals. |
| Databáze: | OpenAIRE |
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