title: Impairment of nitrergic system and delayed gastric emptying in low density lipoprotein receptor deficient female mice.
abstract: BACKGROUND
  In the current study, we have investigated whether low density lipoprotein receptor knockout mice (LDLR-KO), moderate oxidative stress model and cholesteremia burden display gastroparesis and if so whether nitrergic system is involved in this setting. In addition, we have investigated if sepiapterin (SEP) supplementation attenuated impaired nitrergic system and delayed gastric emptying.
  
  
  METHODS
  Gastric emptying and nitrergic relaxation were measured in overnight fasting mice. nNOSα dimerization, anti-oxidant markers such as Nrf2, GCLM, GCLC, HO-1, catalase (CAT), and superoxide dismutase (SOD1) were measured using standard methods. Biopterin levels and intestinal transit time were measured using HPLC and dye migration assay, respectively. Wild type (WT) and LDLR-KO were supplemented with SEP.
  
  
  RESULTS
  In LDLR null stomachs: (i) significant reduction in rate of gastric emptying, gastric pyloric and fundus nitrergic relaxation and nNOSα dimerization, (ii) elevated oxidized biopterins and reduced ratio of BH(4) /BH(2)  + B, (iii) reduced Nrf2 and GCLC protein expression and no change in GCLM, HO-1, CAT, SOD1, and (iv) accelerated small intestinal motility were noticed. Supplementation of SEP restored delayed gastric emptying, impaired pyloric and fundus nitrergic relaxation with restoration of nNOS dimerization and nNOS expression.
  
  
  CONCLUSIONS
  This novel data suggests that hyperlipidemia and/or suppression of selective antioxidants may be a potential cause of developing gastroparesis in diabetic patients.
authors.affiliation: Department of Physiology, Center for Women's Health Research, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd., Nashville, TN 37208, USA. pgangula@mmc.edu
authors.forename: P R
authors.initials: PR
authors.lastname: Gangula
authors.forename: V
authors.initials: V
authors.lastname: Chinnathambi
authors.forename: A B
authors.initials: AB
authors.lastname: Hale
authors.forename: S
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: K M
authors.initials: KM
authors.lastname: Channon
authors.forename: K
authors.initials: K
authors.lastname: Ravella
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001708:Biopterins / Q000737:chemistry / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D005260:Female; D005746:Gastric Emptying / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000502:physiology; D018589:Gastroparesis / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000737:chemistry / Q000378:metabolism; D018384:Oxidative Stress; D011622:Pterins / Q000008:administration & dosage; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011622:Pterins; D011973:Receptors, LDL; D001708:Biopterins; D009569:Nitric Oxide; C016727:sepiapterin; D052248:Nitric Oxide Synthase Type I