Cardiopulmonary Bypass Suppresses Forkhead Box O3 and Downstream Autophagy in the Diabetic Human Heart

Background. Autophagy is an integral component of cellular homeostasis and metabolism. The exact mechanism of impaired autophagy in diabetes mellitus is unknown. Forkhead Box O3 (FOXO3 alpha) is a key regulator of oxidative stress-related responses. We hypothesize FOXO3 alpha is a direct upstream regulator of the autophagy pathway, and its upregulation is compromised in diabetic patients during stress of cardiopulmonary bypass (CPB).Methods. The study enrolled 32 diabetic and 33 nondiabetic patients undergoing a cardiac surgical procedure on CPB. Right atrial tissue and serum samples were collected before and after CPB per protocol. A set of key components were quantitatively assessed and compared by microarray, immunoblotting, and immunohistochemistry studies. Data were analyzed using paired or unpaired student test. A P of <.05 or less was considered significant.Results. Serum microarray showed FOXO3 alpha was upregulated in the diabetic vs nondiabetic group after CPB (P = .033), autophagy-related 4B gene and Beclin 1 gene were greatly upregulated in the nondiabetic group (P = .028 and P = .002, respectively). On immunoblotting, there was upregulation of FOXO3 alpha in the nondiabetic patients after CPB (P = .003). There were increased levels of Beclin-1, Bcl-2, and light chain 3B after CPB in the nondiabetic group only (P = .016, P = .005, P = .002, respectively). Sirtuin 1, Unc-51-like autophagy activating kinase 1 (ULK1), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1 alpha), and mammalian target of rapamycin (mTOR) were not significantly changed in the nondiabetic group after CPB.Conclusions. Compared with nondiabetic patients, there was no significant upregulation of FOXO3 alpha in diabetic patients, which could possibly explain the lack of upregulation of the autophagy process after CPB. FOXO3 alpha could potentially serve as a therapeutic target to improve cellular homeostasis. (C) 2021 by The Society of Thoracic Surgeons