title: Differential impairment of adherens-junction expression/phosphorylation after cardioplegia in diabetic versus non-diabetic patients.
abstract: OBJECTIVE
  Previous animal studies have demonstrated that endothelial adherens-junction molecules are significantly altered in animal myocardium and microvasculature after cardioplegia and cardiopulmonary bypass (CP/CPB). We investigated the effects of diabetes on expression/phosphorylation/localization of vascular endothelial (VE)-cadherin, β- and γ-catenin in human atrial myocardium and coronary vasculature in the setting of CP/CPB.
  
  
  METHODS
  Right atrial tissue was harvested pre- and post-CP/CPB from non-diabetic (ND) [haemoglobin A1c (HbA1c): 5.4 ± 0.15], controlled (CDM) (HbA1c: 6.3 ± 0.14) and uncontrolled diabetic (UDM) (HbA1c: 9.9 ± 0.72) patients (n = 10/group). Expression/phosphorylation/localization of VE-cadherin, β- and γ-catenin were assessed by immunoblotting, immunoprecipitation and immunohistochemistry. In vitro atrial microvascular reactivity was assessed by videomicroscopy in response to the endothelium-dependent vasodilator adenosine 5'-diphosphate (ADP).
  
  
  RESULTS
  There were no significant differences in VE-cadherin protein expression between pre- and post-CP/CPB among groups. There were significant decreases in VE-cadherin densities in vessels of the UDM group versus the ND group at baseline or post-CP/CPB, respectively (P < 0.05). The level of basal phosphorylated VE-cadherin tends to be higher in the UDM compared with the ND group (P < 0.05). CP/CPB induced more phosphorylation of VE-cadherin in all groups (versus pre-CP/CPB; P < 0.05, respectively) and this effect was more pronounced in the UDM group (P < 0.05 versus ND or CDM). The protein levels of both catenins (β and γ) were lower in post-CP/CPB in UDM than ND patients (P < 0.05). There were significant decreases in vasodilatory response to endothelial-dependent vasodilator ADP after CP/CPB (P < 0.05). This alteration was more pronounced in UDM patients (P < 0.05).
  
  
  CONCLUSIONS
  These data suggest that poorly controlled diabetes down-regulates endothelial adherens-junction protein activation/expression/localization in the setting of CP/CPB. The increased tyrosine phosphorylation and deterioration of VE-cadherin indicate the damage of the cell-cell endothelial junctions in the diabetic vessels undergoing CP/CPB and cardiac surgery. These alterations may lead to increase in vascular permeability and endothelial dysfunction and affect outcomes in diabetic patients after cardiac surgery.
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Ashraf A
authors.initials: AA
authors.lastname: Sabe
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Sadek
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Neel R
authors.initials: NR
authors.lastname: Sodha
authors.affiliation: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA fsellke@lifespan.org.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D022005:Adherens Junctions / Q000737:chemistry / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006324:Heart Arrest, Induced / Q000009:adverse effects* / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D010766:Phosphorylation; D051185:gamma Catenin / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051185:gamma Catenin; D000099152:Cadherin 5
keywords: Adherens-junction proteins; Cardioplegia; Cardiopulmonary bypass; Coronary artery bypass grafting; Diabetes; Vascular permeability