Abstract 20521: PGC-1Alpha Upregulation With Alpha-Lipoic Acid Confers Plasticity in the Mediator of Dilation in Healthy and Diseased Human Arterioles
Introduction: Coronary artery disease (CAD) shifts the mediator of flow-induced dilation (FID) from nitric oxide (NO) to mitochondria-derived hydrogen peroxide (H2O2) in the human microcirculation. PGC-1α regulates mitochondrial reactive oxygen species (ROS) production and is decreased in vessels from CAD patients. It is not known whether loss of this regulator contributes to the transition from NO- to H2O2-mediated dilation observed in CAD vessels.
Hypothesis: To determine whether a stimulated increase in PGC-1α levels using alpha-lipoic acid (ALA) can restore NO as the mediator of dilation in CAD vessels.
Methods: non-CAD and CAD human adipose arterioles were incubated overnight with either siRNA to PGC-1α or ALA, an over-the-counter supplement, to decrease or increase PGC-1α, respectively. Vessels were subsequently cannulated on glass micropipettes, and intraluminal pressure was maintained at 60 mmHg. Dilation was elicited by flow in the absence and presence of a nitric oxide synthase inhibitor, L-NAME (10-4 M), a H2O2 inhibitor, PEG-catalase (500 units/mL), or both to determine the mediator of dilation.
Results: Incubation with PGC-1α siRNA in non-CAD vessels produced a transition toward H2O2-mediated dilation (n=6-13; % max dilation, 100 mmHg flow gradient: siRNA 80% vs siRNA+PEG-catalase 0%; P < 0.05). In non-CAD vessels treated with ALA, a trend toward a reduction in FID from control was observed after addition of either L-NAME or PEG-catalase (n=6-10). However, complete inhibition of FID was observed only after addition of both L-NAME and PEG-catalase (n=6; P < 0.05). Similarly, in ALA-treated CAD vessels, neither L-NAME nor PEG-catalase alone was capable of fully abolishing FID (n=8-12; P < 0.05).
Conclusions: Knockdown of PGC-1α in non-CAD vessels produces a CAD phenotype characterized by H2O2-mediated dilation to flow. In contrast to the exclusively NO- or H2O2-mediated FID seen in healthy or diseased conditions, respectively, upregulation of PGC-1α with ALA allows for multiple vasodilators to contribute to FID in vessels from both CAD and non-CAD subjects. PGC-1α upregulation can restore NO as a vasodilator in CAD vessels, thus transitioning away from complete dependence on H2O2.
Author Disclosures: A. Kadlec: None. D. Chabowski: None. A. Beyer: None. D. Gutterman: None.
- © 2016 by American Heart Association, Inc.