Eitezaz Mahmood1, Jelliffe Jeganathan1, Ruby Feng1, Maria Saraf1, Kamal Khabbaz2, Faraz Mahmood2, Senthilnathan Venkatachalam2, David Liu2, Louis Chu2, Samir M Parikh3, Robina Matyal4. 1. Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. 2. Department of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. 3. Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. 4. Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address: rmatyal1@bidmc.harvard.edu.
Abstract
BACKGROUND: The mechanism of mitochondrial dysfunction after cardiopulmonary bypass (CPB) in patients with diabetes mellitus lacks understanding. We hypothesized that impaired beta-oxidation of fatty acids leads to worsened stress response in this patient population after cardiac surgery. METHODS: After Institutional Review Board approval, right atrial tissue samples were collected from 35 diabetic patients and 33 nondiabetic patients before and after CPB. Patients with glycated hemoglobin of 6.0 or greater and a clinical diagnosis of diabetes mellitus were considered to be diabetic. Immunoblotting and microarray analysis were performed to assess protein and gene expression changes. Blots were quantified with ImageJ and analyzed using one-way analysis of variance with multiple Student's t test comparisons after normalization. All p values less than 0.05 were considered significant. Immunohistochemistry was performed for cellular lipid deposition assessment. RESULTS: Diabetic patients had significantly lower levels of PGC-1α before and after CPB (p < 0.01 for both) compared with nondiabetic patients. Several upstream regulators of PGC-1α (SIRT1 and CREB) were significantly higher in nondiabetic patients before CPB (p = 0.01 and 0.0018, respectively). Antioxidant markers (NOX4 and GPX4), angiogenic factors (TGF-β, NT3, and Ang1), and the antiapoptotic factor BCL-xL were significantly lower in diabetic patients after CPB (p < 0.05). The expression of genes supporting mitochondrial energy production (CREB5 and SLC25A40) and angiogenic genes (p < 0.05) was significantly downregulated in diabetic patients after CPB. Immunohistochemistry results showed significantly increased lipid deposition in diabetic myocardial tissue. CONCLUSIONS: Decreased PGC-1α in diabetic patients may lead to impaired mitochondrial function and attenuated antiapoptotic and angiogenic responses after CPB. Therefore, PGC-1α and upstream regulators could serve as a target for improving beta-oxidation in diabetic patients.
BACKGROUND: The mechanism of mitochondrial dysfunction after cardiopulmonary bypass (CPB) in patients with diabetes mellitus lacks understanding. We hypothesized that impaired beta-oxidation of fatty acids leads to worsened stress response in this patient population after cardiac surgery. METHODS: After Institutional Review Board approval, right atrial tissue samples were collected from 35 diabeticpatients and 33 nondiabeticpatients before and after CPB. Patients with glycated hemoglobin of 6.0 or greater and a clinical diagnosis of diabetes mellitus were considered to be diabetic. Immunoblotting and microarray analysis were performed to assess protein and gene expression changes. Blots were quantified with ImageJ and analyzed using one-way analysis of variance with multiple Student's t test comparisons after normalization. All p values less than 0.05 were considered significant. Immunohistochemistry was performed for cellular lipid deposition assessment. RESULTS:Diabeticpatients had significantly lower levels of PGC-1α before and after CPB (p < 0.01 for both) compared with nondiabeticpatients. Several upstream regulators of PGC-1α (SIRT1 and CREB) were significantly higher in nondiabeticpatients before CPB (p = 0.01 and 0.0018, respectively). Antioxidant markers (NOX4 and GPX4), angiogenic factors (TGF-β, NT3, and Ang1), and the antiapoptotic factor BCL-xL were significantly lower in diabeticpatients after CPB (p < 0.05). The expression of genes supporting mitochondrial energy production (CREB5 and SLC25A40) and angiogenic genes (p < 0.05) was significantly downregulated in diabeticpatients after CPB. Immunohistochemistry results showed significantly increased lipid deposition in diabetic myocardial tissue. CONCLUSIONS: Decreased PGC-1α in diabeticpatients may lead to impaired mitochondrial function and attenuated antiapoptotic and angiogenic responses after CPB. Therefore, PGC-1α and upstream regulators could serve as a target for improving beta-oxidation in diabeticpatients.
Authors: Tessa Schillemans; Vinicius Tragante; Buamina Maitusong; Bruna Gigante; Sharon Cresci; Federica Laguzzi; Max Vikström; Mark Richards; Anna Pilbrow; Vicky Cameron; Luisa Foco; Robert N Doughty; Pekka Kuukasjärvi; Hooman Allayee; Jaana A Hartiala; W H Wilson Tang; Leo-Pekka Lyytikäinen; Kjell Nikus; Jari O Laurikka; Sundararajan Srinivasan; Ify R Mordi; Stella Trompet; Adriaan Kraaijeveld; Jessica van Setten; Crystel M Gijsberts; Anke H Maitland-van der Zee; Christoph H Saely; Yan Gong; Julie A Johnson; Rhonda M Cooper-DeHoff; Carl J Pepine; Gavino Casu; Andreas Leiherer; Heinz Drexel; Benjamin D Horne; Sander W van der Laan; Nicola Marziliano; Stanley L Hazen; Juha Sinisalo; Mika Kähönen; Terho Lehtimäki; Chim C Lang; Ralph Burkhardt; Markus Scholz; J Wouter Jukema; Niclas Eriksson; Axel Åkerblom; Stefan James; Claes Held; Emil Hagström; John A Spertus; Ale Algra; Ulf de Faire; Agneta Åkesson; Folkert W Asselbergs; Riyaz S Patel; Karin Leander Journal: Front Physiol Date: 2022-06-23 Impact factor: 4.755