title: Pioglitazone inhibits angiotensin II-induced senescence of endothelial progenitor cell.
abstract: We investigated whether a peroxisome proliferator-activated receptor (PPAR) agonist would effect the angiotensin II (Ang II)-induced senescence of endothelial progenitor cells (EPCs). EPCs were isolated from peripheral blood and characterized. Both reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to assess gp91phox expression and angiotensin type 1 receptor (AT1R) levels. Immunofluorescence of nitrotyrosine provided evidence of peroxynitrite formation. Our data indicate that Ang II increased the expression of gp91phox mRNA, which was significantly diminished by pioglitazone, a PPARgamma agonist. Western blotting revealed that Ang II stimulated an increase in the gp91phox protein, whereas co-treatment with pioglitazone significantly reduced this increase. In addition, pioglitazone also inhibited Ang II-induced peroxynitrite formation. Interestingly, pioglitazone decreased the expressions of AT1R mRNA and protein. The exposure of cultured EPCs to Ang II (100 nmol/L) significantly accelerated the rate of senescence compared to that of the control cells during 14 d in culture, as determined by acidic beta-galactosidase staining. Ang II-induced EPC senescence was significantly inhibited by co-treatment with pioglitazone. Because cellular senescence is critically influenced by telomerase, which elongates telomeres, we also measured telomerase activity by means of PCR-ELISA-based assay. The results showed that Ang II significantly diminished telomerase activity, and this effect was significantly abolished by co-treatment with pioglitazone. In conclusion, pioglitazone inhibited Ang II-induced senescence of EPCs via down-regulation of the expression of AT1R.
authors.affiliation: Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan. t-imani@wakayama-med.ac.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Imanishi
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Akio
authors.initials: A
authors.lastname: Kuroi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ikejima
authors.forename: Takashi
authors.initials: T
authors.lastname: Akasaka
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism; D000077205:Pioglitazone; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D008562:Membrane Glycoproteins; D044140:Receptor, Angiotensin, Type 1; D045162:Thiazolidinediones; D014662:Vasoconstrictor Agents; D013481:Superoxides; D000804:Angiotensin II; D030421:Peroxynitrous Acid; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D019098:Telomerase; D000077205:Pioglitazone