title: Sepiapterin prevents left ventricular hypertrophy and dilatory remodeling induced by pressure overload in rats.
abstract: Uncoupling of nitric oxide (NO) synthase (NOS) has been implicated in left ventricular (LV) hypertrophy (LVH) and dilatory remodeling induced by pressure overload. We investigated whether administration of sepiapterin, a substrate of the salvage pathway of tetrahydrobiopterin synthesis, prevents LVH and dilatory LV remodeling by inhibiting NOS uncoupling and increasing bioavailable NO. Pressure overload was induced in rats by transverse aortic constriction (TAC). Concentric LVH developed during 8 wk after TAC, and dilatory LV remodeling and dysfunction developed between 8 and 16 wk after TAC associated with a decrease in capillary density. Oral administration of sepiapterin or the superoxide/peroxynitrite scavenger N-(2-mercaptopropionyl)-glycine for 8 wk after TAC inhibited oxidative stress, but only sepiapterin increased bioavailable NO and inhibited cardiomyocyte hypertrophy associated with a further increase in capillary density. When sepiapterin was administered between 8 and 16 wk after TAC, cardiomyocyte hypertrophy was regressed and capillary density was restored. This was associated with the inhibition of interstitial fibrosis and dilatory LV remodeling. N-nitro-l-arginine methyl ester abrogated all the beneficial effects of sepiapterin in rats with TAC. These results suggest that sepiapterin prevents concentric LVH and dilatory remodeling after TAC primarily by increasing the bioavailability of NO.
authors.affiliation: Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Yoshioka
authors.affiliation: Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan otanih@takii.kmu.ac.jp.
authors.forename: Hajime
authors.initials: H
authors.lastname: Otani
authors.affiliation: Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shimazu
authors.affiliation: Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan.
authors.forename: Toshiji
authors.initials: T
authors.lastname: Iwasaka
authors.affiliation: Department of Internal Medicine II, Kansai Medical University, Moriguchi City, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
mesh_terms: D000818:Animals; D001011:Aorta / Q000601:surgery; D001708:Biopterins / Q000031:analogs & derivatives / Q000096:biosynthesis; D002196:Capillaries / Q000473:pathology; D048429:Cell Size; D003250:Constriction; D004108:Dilatation, Pathologic / Q000000981:diagnostic imaging / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D009929:Organ Size; D018384:Oxidative Stress / Q000187:drug effects*; D011312:Pressure; D011622:Pterins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; C110658:N-(2-mercaptoproprionyl)-glycine; D011622:Pterins; D013438:Sulfhydryl Compounds; D001708:Biopterins; D009569:Nitric Oxide; C016727:sepiapterin; D019001:Nitric Oxide Synthase; C003402:sapropterin; D005998:Glycine; D019331:NG-Nitroarginine Methyl Ester
keywords: angiogenesis; nitric oxide; tetrahydrobiopterin; transverse aortic constriction