Premium
Down‐regulation of MnSOD via Sirt1/FoxO3a complex increase oxidative stress with cardiac overexpression of Type 5 Adenylyl Cyclase
Author(s) -
Lai Lo,
Yan Lin,
Hu CheLin,
Gao Shumin,
Iwatsubo Kosaku,
Ishikawa Yoshihiro,
Sadoshima Junichi,
Vatner Stephen F.,
Vatner Dorothy E.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1001.16
Subject(s) - oxidative stress , gene knockdown , endocrinology , medicine , adenylyl cyclase , small hairpin rna , catalase , stimulation , myocyte , chemistry , apoptosis , biology , biochemistry
We examined the stress of chronic (7 days) isoproterenol (ISO) stimulation 60mg/kg/day in 3–5 month AC5 Tg mice and WT littermates. Over 30% Tg mice died after day 3 while none of the WT mice died (n=12/group). Oxidative stress induced by chronic ISO stimulation was detected by 8‐Hydroxy‐2′‐deoxyguanosine (8‐OHdG) staining and AC5 Tg hearts showed 27% more positive staining than WT. To further examine whether AC5 Tg mice are less tolerant to oxidative stress, we injected paraquat (PQ), an oxidative stress inducer, and again more positive 8‐OHdG staining was observed in AC5 Tg mice hearts than AC5 KO mice, while the anti‐oxidant MnSOD protein was 40% lower in AC5 Tg than WT. We further hypothesized that inhibition of AC5 activates Sirt1 and FoxO3a, key transcription regulators of MnSOD. Luciferase test showed 3 fold higher FoxO3a transcriptional activity in AC5 knockdown myocytes. Protein expression of MnSOD was 40% decreased in neonatal myocytes infected by both ad‐AC5‐shRNA and ad‐Sirt1‐shRNA compared with AC5 knockdown myocytes. These data suggest that AC5 inhibits the Sirt1/FoxO3a complex thus down‐regulating MnSOD expression, and consequently increasing oxidative stress.