Altered Apoptosis-Related Signaling After Cardioplegic Arrest in Patients With Uncontrolled Type 2 Diabetes Mellitus

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. Methods and 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-&agr;, phospho-PKC-&bgr;1, 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-&agr;, phospho-PKC-&bgr;1, 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.

[1]  R. Ritchie,et al.  Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes , 2012, Diabetologia.

[2]  F. Sellke,et al.  Changes in Microvascular Reactivity After Cardiopulmonary Bypass in Patients With Poorly Controlled Versus Controlled Diabetes , 2012, Circulation.

[3]  A. Saraste,et al.  Cardiomyocyte apoptosis after antegrade and retrograde cardioplegia during aortic valve surgery. , 2011, The Annals of thoracic surgery.

[4]  F. Sellke,et al.  Effects of Cardiopulmonary Bypass on Endothelin-1-Induced Contraction and Signaling in Human Skeletal Muscle Microcirculation , 2010, Circulation.

[5]  Rodica Pop-Busui,et al.  Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial , 2010, The Lancet.

[6]  Walter T Ambrosius,et al.  Effects of medical therapies on retinopathy progression in type 2 diabetes. , 2010, The New England journal of medicine.

[7]  J. Dickenson,et al.  Selective blockade of protein kinase B protects the rat and human myocardium against ischaemic injury , 2010, The Journal of physiology.

[8]  F. Sellke,et al.  Effect of hydrogen sulfide on myocardial protection in the setting of cardioplegia and cardiopulmonary bypass. , 2010, Interactive cardiovascular and thoracic surgery.

[9]  F. Sellke,et al.  Decreased contractile response to endothelin-1 of peripheral microvasculature from diabetic patients. , 2010, Surgery.

[10]  A. Sanz,et al.  Myocardial fibrosis and apoptosis, but not inflammation, are present in long-term experimental diabetes. , 2009, American journal of physiology. Heart and circulatory physiology.

[11]  H. Krum,et al.  Inhibition of Protein Kinase C–β by Ruboxistaurin Preserves Cardiac Function and Reduces Extracellular Matrix Production in Diabetic Cardiomyopathy , 2009, Circulation. Heart failure.

[12]  M. Galiñanes,et al.  Diabetes increases apoptosis and necrosis in both ischemic and nonischemic human myocardium: role of caspases and poly-adenosine diphosphate-ribose polymerase. , 2007, The Journal of thoracic and cardiovascular surgery.

[13]  A. Furnary.  Rationale for glycemic control in cardiac surgical patients: The portland diabetic project , 2006 .

[14]  F. Sellke,et al.  Indices of Apoptosis Activation After Blood Cardioplegia and Cardiopulmonary Bypass , 2006, Circulation.

[15]  F. Sellke,et al.  Molecular Indices of Apoptosis After Intermittent Blood and Crystalloid Cardioplegia , 2005, Circulation.

[16]  F. Sellke,et al.  Bradykinin Preconditioning Improves the Profile of Cell Survival Proteins and Limits Apoptosis After Cardioplegic Arrest , 2005, Circulation.

[17]  F. Sellke,et al.  Improved profile of bad phosphorylation and caspase 3 activation after blood versus crystalloid cardioplegia. , 2004, The Annals of thoracic surgery.

[18]  G. Biondi-Zoccai,et al.  Myocardial ischemia, stunning, inflammation, and apoptosis during cardiac surgery: a review of evidence. , 2004, European Journal of Cardio-Thoracic Surgery.

[19]  J. Schmitt,et al.  Role of apoptosis in myocardial stunning after open heart surgery. , 2002, The Annals of thoracic surgery.

[20]  S. Kirchner,et al.  Endothelial apoptosis is induced by serum of patients after cardiopulmonary bypass. , 2000, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[21]  E. Jones,et al.  Influence of diabetes mellitus on early and late outcome after coronary artery bypass grafting. , 1999, The Annals of thoracic surgery.

[22]  T. Nicotera,et al.  Oxidative damage to DNA in diabetes mellitus , 1996, The Lancet.

[23]  E. Anderson,et al.  Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways. , 2011, American journal of physiology. Heart and circulatory physiology.

[24]  Teven,et al.  MORTALITY FROM CORONARY HEART DISEASE IN SUBJECTS WITH TYPE 2 DIABETES AND IN NONDIABETIC SUBJECTS WITH AND WITHOUT PRIOR MYOCARDIAL INFARCTION , 2000 .