Khurram Owais1, Thomas Huang1, Feroze Mahmood1, Jeffery Hubbard1, Rabya Saraf1, Amit Bardia1, Kamal R Khabbaz2, Yunping Li1, Manoj Bhasin3, Ashraf A Sabe4, Frank Sellke5, Robina Matyal6. 1. Department of Anesthesiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. 2. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. 3. Department of Bioinformatics and Systems Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. 4. Department of Bioinformatics and Systems Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Division of Cardiothoracic Surgery, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island. 5. Division of Cardiothoracic Surgery, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island. 6. Department of Anesthesiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address: rmatya11@bidmc.harvard.edu.
Abstract
BACKGROUND: Cardiopulmonary bypass (CPB) is associated with increased myocardial oxidative stress and apoptosis in diabetic patients. A mechanistic understanding of this relationship could have therapeutic value. To establish a possible mechanism, we compared the activation of the cardioprotective signal transducer and activator of transcription 3 (STAT3) pathway between patients with uncontrolled diabetes (UD) and nondiabetic (ND) patients. METHODS: Right atrial tissue and serum were collected before and after CPB from 80 patients, 39 ND and 41 UD (HbA1c ≥ 6.5), undergoing cardiac operations. The samples were evaluated with Western blotting, immunohistochemistry, and microarray. RESULTS: On Western blot, leptin levels were significantly increased in ND post-CPB (p < 0.05). Compared with ND, the expression of Janus kinase 2 and phosphorylation (p-) of STAT3 was significantly decreased in UD (p < 0.05). The apoptotic proteins p-Bc12/Bc12 and caspase 3 were significantly increased (p < 0.05), antiapoptotic proteins Mcl-1, Bcl-2, and p-Akt were significantly decreased (p < 0.05) in UD compared with ND. The microarray data suggested significantly increased expression of interleukin-6 R, proapoptotic p-STAT1, caspase 9, and decreased expression of Bc12 and protein inhibitor of activated STAT1 antiapoptotic genes (p = 0.05) in the UD patients. The oxidative stress marker nuclear factor-κB was significantly higher (p < 0.05) in UD patients post-CPB compared with the pre-CPB value, but was decreased, albeit insignificantly, in ND patients post-CPB. CONCLUSIONS: Compared with ND, UD myocardium demonstrated attenuation of the cardioprotective STAT3 pathway. Identification of this mechanism offers a possible target for therapeutic modulation.
BACKGROUND: Cardiopulmonary bypass (CPB) is associated with increased myocardial oxidative stress and apoptosis in diabeticpatients. A mechanistic understanding of this relationship could have therapeutic value. To establish a possible mechanism, we compared the activation of the cardioprotective signal transducer and activator of transcription 3 (STAT3) pathway between patients with uncontrolled diabetes (UD) and nondiabetic (ND) patients. METHODS: Right atrial tissue and serum were collected before and after CPB from 80 patients, 39 ND and 41 UD (HbA1c ≥ 6.5), undergoing cardiac operations. The samples were evaluated with Western blotting, immunohistochemistry, and microarray. RESULTS: On Western blot, leptin levels were significantly increased in ND post-CPB (p < 0.05). Compared with ND, the expression of Janus kinase 2 and phosphorylation (p-) of STAT3 was significantly decreased in UD (p < 0.05). The apoptotic proteins p-Bc12/Bc12 and caspase 3 were significantly increased (p < 0.05), antiapoptotic proteins Mcl-1, Bcl-2, and p-Akt were significantly decreased (p < 0.05) in UD compared with ND. The microarray data suggested significantly increased expression of interleukin-6 R, proapoptotic p-STAT1, caspase 9, and decreased expression of Bc12 and protein inhibitor of activated STAT1 antiapoptotic genes (p = 0.05) in the UD patients. The oxidative stress marker nuclear factor-κB was significantly higher (p < 0.05) in UD patients post-CPB compared with the pre-CPB value, but was decreased, albeit insignificantly, in NDpatients post-CPB. CONCLUSIONS: Compared with ND, UD myocardium demonstrated attenuation of the cardioprotective STAT3 pathway. Identification of this mechanism offers a possible target for therapeutic modulation.
Authors: Arun Samidurai; Sean K Roh; Meeta Prakash; David Durrant; Fadi N Salloum; Rakesh C Kukreja; Anindita Das Journal: Cardiovasc Res Date: 2020-11-01 Impact factor: 13.081
Authors: Jake Russell; Eugene F Du Toit; Jason N Peart; Hemal H Patel; John P Headrick Journal: Cardiovasc Diabetol Date: 2017-12-04 Impact factor: 9.951