Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction

Autor: Olivia Ibarra-Sunga, Edmund Ang, Bruce D. Uhal, Rongqi Wang, Alex Zagariya
Rok vydání: 1999
Předmět:
Male
Lung Neoplasms
Physiology
Angiotensinogen
Gene Expression
Angiotensin-Converting Enzyme Inhibitors
Apoptosis
Amino Acid Chloromethyl Ketones
Renin-Angiotensin System
Lisinopril
Tumor Cells
Cultured
Receptor
Membrane Glycoproteins
Receptors
Angiotensin
Angiotensin II
respiratory system
Cell biology
medicine.anatomical_structure
Pulmonary alveolus
Signal Transduction
medicine.drug
Pulmonary and Respiratory Medicine
Programmed cell death
medicine.medical_specialty
Fas Ligand Protein
Enzyme-Linked Immunosorbent Assay
Adenocarcinoma
Cysteine Proteinase Inhibitors
Peptidyl-Dipeptidase A
Biology
Transfection
Antibodies
Neutralization Tests
Physiology (medical)
Internal medicine
medicine
Animals
Humans
RNA
Messenger
fas Receptor
Rats
Wistar
Angiotensin-converting enzyme
Captopril
Cell Biology
Fibrosis
Rats
Pulmonary Alveoli
Antisense Elements (Genetics)
Endocrinology
Cell culture
biology.protein
Zdroj: American Journal of Physiology-Lung Cellular and Molecular Physiology. 277:L1245-L1250
ISSN: 1522-1504
1040-0605
DOI: 10.1152/ajplung.1999.277.6.l1245
Popis: Recent works from this laboratory demonstrated potent inhibition of Fas-induced apoptosis in alveolar epithelial cells (AECs) by the angiotensin-converting enzyme (ACE) inhibitor captopril [B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O. Ibarra-Sunga, M. Papp, K. Flynn, and G. Filippatos. Am. J. Physiol. 275 ( Lung Cell. Mol. Physiol. 19): L1013–L1017, 1998] and induction of dose-dependent apoptosis in AECs by purified angiotensin (ANG) II [R. Wang, A. Zagariya, O. Ibarra-Sunga, C. Gidea, E. Ang, S. Deshmukh, G. Chaudhary, J. Baraboutis, G. Filippatos and B. D. Uhal. Am. J. Physiol. 276 ( Lung Cell. Mol. Physiol. 20): L885–L889, 1999]. These findings led us to hypothesize that the synthesis and binding of ANG II to its receptor might be involved in the induction of AEC apoptosis by Fas. Apoptosis was induced in the AEC-derived human lung carcinoma cell line A549 or in primary AECs isolated from adult rats with receptor-activating anti-Fas antibodies or purified recombinant Fas ligand, respectively. Apoptosis in response to either Fas activator was inhibited in a dose-dependent manner by the nonthiol ACE inhibitor lisinopril or the nonselective ANG II receptor antagonist saralasin, with maximal inhibitions of 82 and 93% at doses of 0.5 and 5 μg/ml, respectively. In both cell types, activation of Fas caused a significant increase in the abundance of mRNA for angiotensinogen (ANGEN) that was unaffected by saralasin. Transfection with antisense oligonucleotides against ANGEN mRNA inhibited the subsequent induction of Fas-stimulated apoptosis by 70% in A549 cells and 87% in primary AECs (both P < 0.01). Activation of Fas increased the concentration of ANG II in the serum-free extracellular medium 3-fold in primary AECs and 10-fold in A549 cells. Apoptosis in response to either Fas activator was completely abrogated by neutralizing antibodies specific for ANG II ( P < 0.01), but isotype-matched nonimmune immunoglobulins had no significant effect. These data indicate that the induction of AEC apoptosis by Fas requires a functional renin-angiotensin system in the target cell. They also suggest that therapeutic control of AEC apoptosis is feasible through pharmacological manipulation of the local renin-angiotensin system.
Databáze: OpenAIRE
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