Faculty Collaboration Database

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. Hypertension 2017 Jul;70(1):166-173

Date

05/24/2017

Pubmed ID

28533333

Pubmed Central ID

PMC5485836

DOI

10.1161/HYPERTENSIONAHA.117.09289

Scopus ID

2-s2.0-85019610110 (requires institutional sign-in at Scopus site)   37 Citations

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 (N^G-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.

Author List

Kadlec AO, Chabowski DS, Ait-Aissa K, Hockenberry JC, Otterson MF, Durand MJ, Freed JK, Beyer AM, Gutterman DD

Authors

Andreas M. Beyer PhD Associate Professor in the Medicine department at Medical College of Wisconsin
Matt Durand PhD Associate Professor in the Physical Medicine and Rehabilitation department at Medical College of Wisconsin
Julie K. Freed MD, PhD Vice Chair, Associate Professor in the Anesthesiology department at Medical College of Wisconsin
Mary F. Otterson MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Biological Availability
Catalase
Coronary Artery Disease
Coronary Vessels
Humans
Hydrogen Peroxide
Microcirculation
Models, Biological
Nitric Oxide
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Polyethylene Glycols
Statistics as Topic
Vasodilation
Vasodilator Agents