P1890Pioglitazone inhibits diabetes-induced atrial mitochondrial oxidative stress and improves mitochondrial biogenesis, dynamics and function through the PGC-1 signaling pathway

Abstract

Background Oxidative stress contributes to adverse atrial remodeling in diabetes mellitus. This can be prevented by the PPAR-γ agonist pioglitazone through its anti-oxidant and anti-inflammatory effects. Purpose In this study, the molecular mechanisms underlying these effects were investigated. Methods Rabbits were randomly divided into control (C), diabetic (DM), and pioglitazone-treated DM (Pio) groups. Echocardiographic, hemodynamic, electrophysiological, intracellular Ca2+ properties were measured. Serum PPAR-γ levels, serum and tissue oxidative stress and inflammatory markers, mitochondrial morphology, reactive oxygen species (ROS) production rate, respiratory function, and mitochondrial membrane potential (MMP) levels were measured. Protein expression of pro-fibrotic marker transforming growth factor β1 (TGF-β1), and the mitochondrial proteins (PGC-1α, fission and fusion-related proteins) were measured. Results Compared with controls, the DM group demonstrated larger left atrial diameter and fibrosis area associated with a higher incidence of inducible AF. Lower serum PPAR-γ level was associated with lower PGC-1α, higher NF-κB and higher TGF-β1 expression. Mn-SOD protein was not different but lower mitochondrial fission- and fusion-related proteins were detected. Mitochondrial swelling, higher mitochondrial ROS, lower respiratory control rate, lower MMP and higher intracellular Ca2+ transients were observed. In the Pio group, reversal of structural remodeling and lower inducible AF incidence were associated with higher PPAR-γ and PGC-1α. NF-κB and TGF-β1 were lower and biogenesis, fission and fusion-related protein were higher. Mitochondrial structure and function, and intracellular Ca2+ transients were improved. In HL-1 cell line, transfected with PGC-1α siRNA blunted the effect of pioglitazone on Mn-SOD protein expression and MMP collapse in H2O2-treated cells. Conclusion Diabetes mellitus induces adverse atrial structural and electrophysiological remodeling, abnormal Ca2+ handling and mitochondrial damage and dysfunction. Pioglitazone prevented these abnormalities through the PPAR-γ/PGC-1α pathway. Acknowledgement/Funding National Natural Science Foundation of China (No 81570298, 81270245, 30900618 to T.L.)

Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway

“…The content of this manuscript has been presented in part at the ESC Congress 2019 (Liu et al, 2019).…”