PGC-1α (Peroxisome Proliferator–Activated Receptor γ Coactivator 1-α) Overexpression in Coronary Artery Disease Recruits NO and Hydrogen Peroxide During Flow-Mediated Dilation and Protects Against Increased Intraluminal Pressure

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Abstract

Blood flow through healthy human vessels releases NO to produce vasodilation, whereas in patients with coronary artery disease (CAD), the mediator of dilation transitions to mitochondria-derived hydrogen peroxide (mtH2O2). Excessive mtH2O2 production contributes to a proatherosclerotic vascular milieu. Loss of PGC-1α (peroxisome proliferator–activated receptor γ coactivator 1α) is implicated in the pathogenesis of CAD. We hypothesized that PGC-1α suppresses mtH2O2 production to reestablish NO-mediated dilation in isolated vessels from patients with CAD. Isolated human adipose arterioles were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the presence of PEG (polyethylene glycol)–catalase (H2O2 scavenger) or L-NAME (NG-nitro-L-arginine methyl ester; NOS inhibitor). In contrast to the exclusively NO- or H2O2-mediated dilation seen in either non-CAD or CAD conditions, respectively, flow-mediated dilation in CAD vessels was sensitive to both L-NAME and PEG-catalase after PGC-1α upregulation using ZLN005 and α-lipoic acid. PGC-1α overexpression in CAD vessels protected against the vascular dysfunction induced by an acute increase in intraluminal pressure. In contrast, downregulation of PGC-1α in non-CAD vessels produces a CAD-like phenotype characterized by mtH2O2-mediated dilation (no contribution of NO). Loss of PGC-1α may contribute to the shift toward the mtH2O2-mediated dilation observed in vessels from subjects with CAD. Strategies to boost PGC-1α levels may provide a therapeutic option in patients with CAD by shifting away from mtH2O2-mediated dilation, increasing NO bioavailability, and reducing levels of mtH2O2. Furthermore, increased expression of PGC-1α allows for simultaneous contributions of both NO and H2O2 to flow-mediated dilation.

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