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PGC-1alpha Overexpression in Coronary Artery Disease Recruits Nitric Oxide and Hydrogen Peroxide during Flow-mediated Dilation and Protects Against Increased Intraluminal Pressure
Blood flow through healthy human vessels releases nitric oxide (NO) to produce vasodilation, whereas in patients with coronary artery disease (CAD), the mediator of dilation transitions to mitochondria-derived hydrogen peroxide (
mt
H
2
O
2
). Excessive
mt
H
2
O
2
production contributes to a proatherosclerotic vascular milieu. Loss of PGC-1α is implicated in the pathogenesis of CAD. We hypothesized that PGC-1α suppresses
mt
H
2
O
2
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-catalase (H
2
O
2
scavenger) or L-NAME (NOS inhibitor). In contrast to the exclusively NO- or H
2
O
2
-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 alpha-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
mt
H
2
O
2
-mediated dilation (no contribution of NO). Loss of PGC-1α may contribute to the shift towards the
mt
H
2
O
2
-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
mt
H
2
O
2
-mediated dilation, increasing NO bioavailability, and reducing levels of
mt
H
2
O
2
. Furthermore, increased expression of PGC-1α allows for simultaneous contributions of both NO and H
2
O
2
to flow-mediated dilation.