Abstract 4887: The Thiazolidinedione Pioglitazone up-regulates Vascular Telomere Regulating Proteins and Prevents Cellular Senescence in Mice
Background: PPAR-γ agonists (thiazolidinediones, TZDs) are used for the treatment of diabetes mellitus. Experimental and clinical data implicate that TZDs may mediate vascular effects in addition to the lowering of blood glucose. Aging is the predominant risk factor for the development of cardiovascular disease. Telomeres and telomere-associated proteins affect cellular aging, senescence and survival. We hypothesized that TZDs may regulate vascular telomere biology.
Methods and Results: C57/Bl6 mice (Age 12 weeks, male) were subjected to treatment with pioglitazone (20mg/kg i.p. daily) or vehicle for 4 weeks. Telomere repeat amplification protocol (TRAP) assays showed a marked increase in aortic telomerase activity in the pioglitazone group to 319±30% vs. vehicle. Western blots demonstrated an increased protein levels of telomere-repeat binding factor 2 (367±20%) and reduced expression of the senescence- and apoptosis-related factors p16 (65±11%) and p53 (53±28%). Similar observations were made in mononuclear cells isolated from the spleen. Additionally, the number of spleen-derived endothelial progenitor cells was up-regulated in TZD-treated mice (550±36%). The physiologic significance of these findings was tested by induction of vascular oxidative stress in-vivo by injection of lipopolysaccharide (LPS, 125mg, i.p.). Endothelial apoptosis in the thoracic aorta was quantitated by hairpin oligonucleotid assays. LPS increased apotosis to 576±16 % of vehicle which was potently prevented in TZD-treated animals (Pio+LPS 241±12 %). All reported effects were significant with p<0.05, n = 6 –12 per group.
Conclusions: TZD treatment up-regulates telomerase activity, telomere-capping proteins and induces anti-senescent effects in the vascular wall. The reduction of LPS-induced endothelial apoptosis indicates that the observed effects are physiologically relevant in mice. Our data improve the molecular understanding of the vascular effects of TZDs.