Abstract 11474: Deficiency of Senescence Marker Protein-30 Impairs Collateral Growth by Supressing Nitric Oxide Bioactivity Under Ischemia
Aging impairs collateral growth under ischemia and reduces the expression of VEGF, however the exact mechanism is unclear. Senescence marker protein-30 (SMP30) decreases with aging. Mice with SMP30 deficiency, a model of aging, have a short lifespan with increased oxidant stress. To elucidate the effect of SMP30 on ischemia-induced collateral growth, we examined the recovery of cutaneous blood flow (CBF) after femoral artery ligation by laser Doppler imaging in mice. Recoveries of CBF and tissue capillary density were suppressed in SMP30 knockout (KO) mice compared to those of wild type (WT) mice (Figure). Acetylcholine (ACh, 1 μM)-induced NO generation, total thiol and reduced glutathione (GSH) levels in aorta of SMP30 KO mice were lower than those of WT mice (NO: 2.6±4.5 vs. 86.2±9.2 nM; total thiol: 6.3±1.6 vs. 33.2±4.6 nmol/mg/protein; GSH: 5.1±0.8 vs. 18.6±2.1 nmol/mg/protein; P<0.01, respectively). Superoxide generation and NADPH oxidase activity were greater in aorta of SMP30 KO mice compared to that of WT mice (superoxide level: 3.3±0.5 vs. 1.6±0.2 nmol/mg protein; NADPH oxidase activity: 3240±254 vs. 982±106 RLU; P<0.01, respectively). Asymmetric dimethylarginine (ADMA) level was higher in aorta of SMP30 KO mice than that of WT mice (6.4±0.8 vs. 2.4±0.4 nmol/mg protein, P<0.01). VEGF content in the crural muscle in SMP30 KO mice did not increase in 14 days post-ischemia compared to that in pre-ischemia (SMP30 KO mice 1.1±0.2 fold vs. WT mice 2.2±0.3 fold, P<0.01). Akt phosphorylation in the crural muscle was attenuated in SMP30 KO mice compared to that of WT mice (p-Akt/Akt: SMP30 KO mice 0.4±0.3 vs. WT mice 1.2±0.4, P<0.01). Thus, SMP30 deficiency exacerbates oxidant stress due to NADPH oxidase activation, which leads to the rarefaction of collateral growth induced by ischemia related to Akt-VEGF pathway. These results suggest that the decrease of SMP30 in aging impairs VEGF/NO-dependent angiogenesis associated with overproduction of superoxide.
Author Disclosures: H. Yamauchi: None. S. Saitoh: None. T. Owada: None. Y. Takeishi: None.
- © 2014 by American Heart Association, Inc.