Decreased PGC-1α Post-Cardiopulmonary Bypass Leads To Impaired Oxidative Stress In Diabetic Patients.

BACKGROUND: The mechanism of mitochondrial dysfunction following cardiopulmonary bypass (CPB) in diabetics 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 IRB approval, right atrial tissue samples were collected from 35 diabetic and 33 non-diabetics pre- and post-CPB. Patients with HbA1c ≥ 6.0 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 ANOVA with multiple t-test comparisons after normalization. P-values < 0.05 were considered significant. Immunohistochemistry was performed for cellular lipid deposition assessment.

RESULTS: Diabetics had significantly lower levels of PGC-1α pre- and post-CPB (p < 0.01 for both) compared to non-diabetics. Several upstream regulators of PGC-1α (SIRT1 and CREB) were significantly higher in non-diabetics pre-CPB (p = 0.01 and 0.0018, respectively). Antioxidant markers (NOX4 and GPX4), angiogenic factors (TGF-β, NT3, and Ang1), and the anti-apoptotic factor Bcl-xL were significantly lower in diabetics post-CPB (p < 0.05). The expression of genes supporting mitochondrial energy production (CREB5 and SLC25A40) and angiogenic genes (p < 0.05) was significantly down-regulated in diabetics post-CPB. Immunohistochemistry results showed significantly increased lipid deposition in diabetic myocardial tissue.

CONCLUSIONS: Decreased PGC-1α in diabetics may lead to impaired mitochondrial function and attenuated anti-apoptotic and angiogenic responses post-CPB. PGC-1α and upstream regulators could serve as a target for improving beta-oxidation in diabetics.