A PPARα promoter variant impairs ERR-dependent transactivation and decreases mortality after acute coronary ischemia in patients with diabetes.

Sharon Cresci
Janice M Huss
Amber L Beitelshees
Philip G Jones
Matt R Minton
Gerald W Dorn
Daniel P Kelly
John A Spertus
Howard L McLeod

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Publication date

September 2010

DOI

10.1371/journal.pone.0012584

Publisher

Public Library of Science (PLoS)

ISSN

1932-6203

Journal

issn:1932-6203

Citation count (estimate)

Abstract

Activation of peroxisome proliferator-activated receptor alpha (PPARα) occurs in animal models of diabetes (DM) and is implicated in pathological responses to myocardial ischemia. Using bioinformatics, we identified a single nucleotide polymorphism (SNP) in the PPARα gene promoter (PPARA -54,642 G>A; rs135561) that altered the consensus sequence for a nuclear receptor binding site. Electrophoretic mobility shift assays showed that the domain bound two known PPARA transcriptional activators, estrogen-related receptor (ERR)-α and -γ and that PPARA G bound with greater affinity than PPARA A (>2-fold; P<0.05). Likewise, promoter-reporter analyses showed enhanced transcriptional activity for PPARA G vs. PPARA A for both ERR-α and -γ (3.1 vs.1.9-...