title: Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice.
abstract: OBJECTIVE
  Sodium-glucose cotransporter 1 (SGLT1) is thought to be expressed in the heart as the dominant isoform of cardiac SGLT, although more information is required to delineate the subtypes of SGLTs in human hearts. Moreover, the functional role of SGLTs in the heart remains to be fully elucidated. We herein investigated whether SGLT1 is expressed in human hearts and whether SGLTs significantly contribute to cardiac energy metabolism during ischemia-reperfusion injury (IRI) via enhanced glucose utilization in mice.
  
  
  RESULTS
  We determined that SGLT1 was highly expressed in both human autopsied hearts and murine perfused hearts, as assessed by immunostaining and immunoblotting with membrane fractionation. To test the functional significance of the substantial expression of SGLTs in the heart, we studied the effects of a non-selective SGLT inhibitor, phlorizin, on the baseline cardiac function and its response to ischemia-reperfusion using the murine Langendorff model. Although phlorizin perfusion did not affect baseline cardiac function, its administration during IRI significantly impaired the recovery in left ventricular contractions and rate pressure product, associated with an increased infarct size, as demonstrated by triphenyltetrazolium chloride staining and creatine phosphokinase activity released into the perfusate. The onset of ischemic contracture, which indicates the initiation of ATP depletion in myocardium, was earlier with phlorizin. Consistent with this finding, there was a significant decrease in the tissue ATP content associated with reductions in glucose uptake, as well as lactate output (indicating glycolytic flux), during ischemia-reperfusion in the phlorizin-perfused hearts.
  
  
  CONCLUSIONS
  Cardiac SGLTs, possibly SGLT1 in particular, appear to provide an important protective mechanism against IRI by replenishing ATP stores in ischemic cardiac tissues via enhancing availability of glucose. The present findings provide new insight into the significant role of SGLTs in optimizing cardiac energy metabolism, at least during the acute phase of IRI.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kashiwagi
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nagoshi
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Toshikazu D
authors.initials: TD
authors.lastname: Tanaka
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ito
authors.affiliation: Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Harada
authors.affiliation: Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikegami
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Ryuko
authors.initials: R
authors.lastname: Anzawa
authors.affiliation: Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Yoshimura
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D008297:Male; D008813:Mice, Inbred ICR; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D010477:Perfusion; D010695:Phlorhizin / Q000378:metabolism*; D020127:Recovery of Function; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism*
chemical_list: C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; D000255:Adenosine Triphosphate; D010695:Phlorhizin; D005947:Glucose