title: Altered apoptosis-related signaling after cardioplegic arrest in patients with uncontrolled type 2 diabetes mellitus.
abstract: BACKGROUND
  We investigated the effects of cardioplegic arrest and reperfusion (CP/Rep) on myocardial apoptosis and key apoptotic mediators, such as apoptosis-inducing factor, caspase 3, caspase 8, caspase 9, poly(adenosine diphosphate-ribose) polymerase, B-cell lymphoma 2 (Bcl-2) family proteins, and protein kinase C (PKC), in uncontrolled type 2 diabetic, controlled type 2 diabetic, and nondiabetic patients.
  
  
  RESULTS
  Right atrial tissue was harvested pre- and post-CP/Rep from uncontrolled type 2 diabetic patients (hemoglobin A1c=9.6 ± 0.25), controlled type 2 diabetic patients (hemoglobin A1c=6.5 ± 0.15), and nondiabetic patients (hemoglobin A1c=5.4 ± 0.12) undergoing coronary artery bypass grafting (n=8/group). Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was used for the identification of apoptotic cells. Total and modified apoptosis-inducing factor, Bcl-2 family proteins, phospho-PKC-α, phospho-PKC-β1, and poly(adenosine diphosphate-ribose) polymerase were quantified by immunoblotting or immunohistochemistry. At baseline, the number of apoptotic cells and expression of total apoptosis-inducing factor, Bcl-2, Bak, and Bax in the pre-CP/Rep atrial tissue from uncontrolled type 2 diabetic patients were significantly increased compared with those of nondiabetic or controlled type 2 diabetic patients (P<0.05). After CP/Rep, the amount of apoptotic cells, apoptosis-inducing factor, phospho-Bad, phospho-PKC-α, phospho-PKC-β1, and cleaved poly(adenosine diphosphate-ribose) polymerase in post-CP/Rep atrial tissue were increased in all 3 groups compared with pre-CP/Rep. These increases after CP/Rep were more pronounced in the uncontrolled type 2 diabetic group. In addition, there were significant increases in the expression of cleaved caspase 8 and caspase 9 in the basal and post-CP/Rep atrium of uncontrolled type 2 diabetic group compared with nondiabetic or controlled type 2 diabetic group.
  
  
  CONCLUSIONS
  Uncontrolled diabetes mellitus is associated with increases in myocardial apoptosis and expression of key apoptosis mediators at baseline and in the setting of CP/Rep.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Nikola
authors.initials: N
authors.lastname: Dobrilovic
authors.forename: Louis M
authors.initials: LM
authors.lastname: Chu
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Arun K
authors.initials: AK
authors.lastname: Singh
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000502:physiology*; D020517:Atrial Appendage / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D002314:Cardioplegic Solutions / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery; D005260:Female; D006323:Heart Arrest / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D006324:Heart Arrest, Induced / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D010865:Pilot Projects
chemical_list: D002314:Cardioplegic Solutions
keywords: apoptosis; cardioplegia; cardiopulmonary bypass; coronary artery bypass surgery; diabetes mellitus
references.citation: Circulation. 2005 Aug 30;112(9 Suppl):I184-9
references.pmid: 16159813
references.citation: Ann Thorac Surg. 2011 Oct;92(4):1351-7
references.pmid: 21958782
references.citation: Circulation. 2010 Sep 14;122(11 Suppl):S150-5
references.pmid: 20837906
references.citation: Ann Thorac Surg. 2004 Apr;77(4):1384-9; discussion 1389-90
references.pmid: 15063271
references.citation: J Physiol. 2010 Jun 15;588(Pt 12):2173-91
references.pmid: 20403980
references.citation: Circulation. 2012 Sep 11;126(11 Suppl 1):S73-80
references.pmid: 22965996
references.citation: Ann Thorac Surg. 2002 Apr;73(4):1229-35
references.pmid: 11996268
references.citation: N Engl J Med. 1998 Jul 23;339(4):229-34
references.pmid: 9673301
references.citation: Cardiovasc Toxicol. 2001;1(3):181-93
references.pmid: 12213971
references.citation: Diabetologia. 2012 Dec;55(12):3369-81
references.pmid: 23001375
references.citation: J Thorac Cardiovasc Surg. 2007 Jul;134(1):124-31, 131.e1-3
references.pmid: 17599497
references.citation: Am J Physiol Heart Circ Physiol. 2009 Dec;297(6):H2109-19
references.pmid: 19820199
references.citation: Lancet. 2010 Aug 7;376(9739):419-30
references.pmid: 20594588
references.citation: Circulation. 2006 Jul 4;114(1 Suppl):I257-63
references.pmid: 16820582
references.citation: Interact Cardiovasc Thorac Surg. 2010 Apr;10(4):506-12
references.pmid: 20051450
references.citation: Am J Physiol Heart Circ Physiol. 2011 Jan;300(1):H118-24
references.pmid: 21076025
references.citation: Ann Thorac Surg. 1999 Apr;67(4):1045-52
references.pmid: 10320249
references.citation: N Engl J Med. 2010 Jul 15;363(3):233-44
references.pmid: 20587587
references.citation: Surgery. 2011 Feb;149(2):247-52
references.pmid: 20727565
references.citation: Lancet. 1996 Feb 17;347(8999):444-5
references.pmid: 8618487
references.citation: Eur J Cardiothorac Surg. 2000 Nov;18(5):589-93
references.pmid: 11053822
references.citation: Eur J Cardiothorac Surg. 2004 Mar;25(3):304-11
references.pmid: 15019653
references.citation: Circulation. 2005 Aug 30;112(9 Suppl):I190-5
references.pmid: 16159814