title: Antioxidant therapy attenuates myocardial telomerase activity reduction in superoxide dismutase-deficient mice.
abstract: Oxidative stress plays a pathological role in the development of heart failure. This study examined telomere biology in heart/muscle-specific manganese superoxide dismutase-deficient mice (H/M-SOD2(-/-)), which develop progressive congestive heart failure and exhibit pathology typical of dilated cardiomyopathy. EUK-8 (25mg/kg/day), a superoxide dismutase and catalase mimetic, was administered to H/M-SOD2(-/-) mice for four weeks beginning at 8 weeks of age. Telomere length, telomerase activity, telomere-associated proteins, and cell death signals were assessed in hearts from control wild-type mice (H/M-Sod2 (lox/ lox)) and H/M-SOD2(-/-) mice either treated or untreated with EUK-8. While cardiac function was unchanged in these experimental mice, the end-diastolic dimension in H/M-SOD2(-/-) mice was notably dilated and could be significantly reduced by EUK-8 treatment. At the end of the study, no shortening of telomere length was observed in heart tissues from all mice tested, but telomerase activity was decreased in heart tissue from H/M-SOD2(-/-) mice compared to control mice. Protein expression for telomerase reverse transcriptase and telomere repeat binding factor 2 was also downregulated in H/M-SOD2(-/-) heart tissue as was expression of phospho-Akt, insulin-like growth factor, and endothelial nitric oxide synthase. Expression levels of Sirt1, a lifespan modulator, were enhanced while FoxO3a was depressed in H/M-SOD2(-/-) hearts. All of the changes seen in H/M-SOD2(-/-) heart tissue could be inhibited by EUK-8 treatment. Taken together, the results suggest that oxidant stress might affect myocardial telomerase activity and telomere-associated proteins. Telomerase may therefore play a pivotal role in antioxidant defense mechanisms, and may be useful as a novel therapeutic tool for treating human heart failure.
authors.affiliation: Division of Molecular and Clinical Gerontology, Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Beppu 874-0838, Japan. makinon@beppu.kyushu-u.ac.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Makino
authors.forename: Toyoki
authors.initials: T
authors.lastname: Maeda
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Oyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Koji
authors.initials: K
authors.lastname: Mimori
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D015139:Blotting, Southern; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D004452:Echocardiography; D005029:Ethylenediamines / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D009942:Organometallic Compounds / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000187:drug effects / Q000378:metabolism
chemical_list: D000975:Antioxidants; D005029:Ethylenediamines; D009942:Organometallic Compounds; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II); D013482:Superoxide Dismutase; D019098:Telomerase