• Ju-Woo Nho, Debolina Banerjee, Dwight D Harris, Christopher Stone, Hang Xing, Meghamsh Kanuparthy, Janelle Li, Frank W Sellke, and Jun Feng.
• Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, 2 Dudley Street, MOC 360. Providence RI 02905.
• J. Am. Coll. Surg. 2024 Dec 9.

BackgroundCardioplegic ischemia/reperfusion (I/R) injury poses substantial challenges during postoperative recovery, with diabetic patients particularly susceptible to adverse events. Using a model entailing the subjection of human coronary artery endothelial cells (HCAECs) to simulated cardioplegic I/R, we investigated the potential of protein kinase c β (PKC-β) inhibition to augment cellular survival in this context.Study DesignHCAECs were isolated from harvested coronary arteries of diabetic (D) and nondiabetic (C) patients (N = 4 per group). HCAECs were either cultured in normoxic conditions without drug (D and C), subjected to hypoxia/reoxygenation alone (DH and CH), or subjected to hypoxia/reoxygenation and the PKC-β inhibitor LY333531 (DHT and CHT). Molecular signaling was assessed using immunoblotting.ResultsSimulated I/R decreased anti-apoptotic phosphorylated protein kinase b (p-Akt, p = 0.04) and p-Akt:Akt ratio (p = 0.004) in CH versus C, with PKC-β inhibition restoring expression in CHT (p ≤ 0.04). Treatment also increased p-Akt:Akt ratio in DHT versus D (p = 0.03). Anti-apoptotic inducible nitric oxide synthase increased in CHT versus CH (p = 0.003), and pro-apoptotic phosphor-FOXO:FOXO ratio decreased in CHT versus CH (p = 0.001). I/R elevated Bcl-2-associated agonist of cell death (BAD) in CH versus C (p = 0.01), but PKC-β inhibition increased anti-apoptotic p-BAD (p = 0.001) and p-BAD:BAD ratio (p = 0.03) in CHT. I/R also increased cleaved PARP (p < 0.001) and cleaved caspase 3 (p < 0.001) in DH versus D, both of which were reversed by treatment (p < 0.001 for DHT versus DH).ConclusionPKC-β inhibitor treatment increased pro-survival signaling and decreased pro-apoptotic signaling in nondiabetic and diabetic HCAECs subjected to simulated I/R, with mechanistic differences observed between these cohorts.Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.

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