A PPARα Promoter Variant Impairs ERR-Dependent Transactivation and Decreases Mortality after Acute Coronary Ischemia in Patients with DiabetesReport as inadecuate




A PPARα Promoter Variant Impairs ERR-Dependent Transactivation and Decreases Mortality after Acute Coronary Ischemia in Patients with Diabetes - Download this document for free, or read online. Document in PDF available to download.

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-fold; P<0.05. Since PPARα activation impairs post-ischemic cardiac function in experimental models of DM, we tested whether decreased PPARA transcription in PPARA A carriers favorably impacted outcome after acute coronary ischemia in 705 patients hospitalized with acute coronary syndromes ACS; 552 Caucasian, 106 African American. PPARA A allele frequencies were similar to non-diseased subjects. However, PPARA genotype correlated with 5-year mortality in diabetic 22.2% AA vs. 18.8% AG vs. 39.5% GG; P = 0.008, but not non-diabetic P = 0.96 subjects genotype by diabetes interaction P = 0.008. In the diabetic ACS subjects, PPARA A carriers had strikingly reduced all-cause mortality compared to PPARA G homozygotes, unadjusted HR 0.44, 95% CI 0.26–0.75; P = 0.003; adjusted HR 0.48, 95% CI 0.27–0.83; P = 0.009. Consistent with previous descriptions of PPARα in experimental models and human disease, we describe a novel PPARA promoter SNP that decreases transcriptional activation of PPARA and protects against mortality in diabetic patients after ACS.



Author: Sharon Cresci , Janice M. Huss, Amber L. Beitelshees, Philip G. Jones, Matt R. Minton, Gerald W. Dorn II, Daniel P. Kelly, John A

Source: http://plos.srce.hr/



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