title: Thiamine attenuates the hypertension and metabolic abnormalities in CD36-defective SHR: uncoupling of glucose oxidation from cellular entry accompanied with enhanced protein O-GlcNAcylation in CD36 deficiency.
abstract: OBJECTIVE
  The spontaneous hypertensive rat (SHR) is a widely studied model of hypertension that exhibits metabolic abnormalities, which share features with the human metabolic syndrome. Genetic linkage studies have revealed a defective CD36 gene, encoding a membrane fatty acid (FA) transporter, in hyperinsulinemia of the SHR. However, there is no unifying mechanism that can explain these phenotypes as a consequence of a defective CD36 gene. Impaired fatty acid uptake is compensated by increased glucose uptake. We hypothesized that (1) the abundant intracellular glucose is not oxidized proportionally and (2) the correction of the uncoupling of glucose oxidation to its cellular entry might be effective against the pathophysiology of CD36-defective SHR. Therefore, we attempted to activate glucose oxidation with the repletion of thiamine, a coenzyme for multiple steps of glucose metabolism.
  
  
  RESULTS
  In one series of experiments, intracellular glucose fate was assessed by the ratio of [(14)C]glucose/[(3)H]deoxyglucose radioactivity, which suggested that glucose oxidation was uncoupled from its cellular entry in SHR. Protein O-GlcNAcylation was intense in the hearts of CD36-defective SHR compared with that of wild-type CD36 rats [Wister Kyoto rats (WKY)], indicating the shunt of glucose through the hexosamine biosynthetic pathway (HBP). In another series of studies, 4-week-old SHR were maintained with water containing 0.2% thiamine for 10 weeks. Systolic blood pressure, plasma insulin and norepinephrine levels were significantly lower in the thiamine-group, as compared with the untreated-group. In epididymal adipose tissue, thiamine repletion down-regulated the expression levels of mRNA transcripts for UDP-N-acetylglucosamine:peptide glycosyltransferase, angiotensinogen, angiotensin type 1 receptor, transforming growth factor-beta1 and plasminogen activator inhibitor-1.
  
  
  CONCLUSIONS
  The hearts of CD36-defective SHR exhibited uncoupling of glucose oxidation from its cellular entry, accompanied with the enhanced protein O-GlcNAcylation, suggesting increased glucose shunt through the HBP. Thiamine repletion in CD36-defective SHR resulted in (1) the correction of the uncoupling of glucose oxidation to its cellular entry, concomitant with reduced protein O-GlcNAcylation, (2) the down-regulation of the expression of mRNAs involved in HBP, the renin-angiotensin system and adipokines in epididymal adipose tissue, and (3) the attenuation of the hypertension and hyperinsulinemia. We propose that interventions targeting glucose oxidation with thiamine repletion may provide a novel adjunctive approach to attenuate metabolic abnormalities and related hypertension.
authors.affiliation: Third Division, Department of Internal Medicine, Osaka Medical College, Osaka, Japan. in3024@poh.osaka-med.ac.jp
authors.forename: Takao
authors.initials: T
authors.lastname: Tanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Sohmiya
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Kono
authors.forename: Fumio
authors.initials: F
authors.lastname: Terasaki
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Horie
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ohkaru
authors.forename: Michiko
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Mizuo
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kitaura
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000215:Acylation; D000818:Animals; D001483:Base Sequence; D018955:CD36 Antigens / Q000502:physiology*; D017931:DNA Primers; D005947:Glucose / Q000378:metabolism*; D006031:Glycosylation; D006973:Hypertension / Q000517:prevention & control*; D007150:Immunohistochemistry; D008659:Metabolic Diseases / Q000517:prevention & control*; D010084:Oxidation-Reduction; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013831:Thiamine / Q000627:therapeutic use*
chemical_list: D018955:CD36 Antigens; D017931:DNA Primers; D005947:Glucose; D000117:Acetylglucosamine; D013831:Thiamine