PGC-1α and ERRα target gene downregulation is a signature of the failing human heart

Abstract

Heart failure is a cause of significant morbidity and mortality in developed nations, and results from a complex interplay between genetic and environmental factors. To discover gene regulatory networks underlying heart failure, we analyzed DNA microarray data based on left ventricular freewall myocardium from 59 failing (32 ischemic cardiomyopathy, 27 idiopathic dilated cardiomyopathy) and 33 non-failing explanted human hearts from the Cardiogenomics Consortium. In particular, we sought to investigate cardiac gene expression changes at the level of individual genes, as well as biological pathways which contain groups of functionally related genes. Utilizing a combination of computational techniques, including Comparative Marker Selection and Gene Set Enrichment Analysis, we identified a subset of downstream gene targets of the master mitochondrial transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), whose expression is collectively decreased in failing human hearts. We also observed decreased expression of the key PGC-1α regulatory partner, estrogen-related receptor α (ERRα), as well as ERRα target genes which may participate in the downregulation of mitochondrial metabolic capacity. Gene expression of the antiapoptotic Raf-1/extracellular signal-regulated kinase (ERK) pathway was decreased in failing hearts. Alterations in PGC-1α and ERRα target gene sets were significantly correlated with an important clinical parameter of disease severity -left ventricular ejection fraction, and were predictive of failing vs. non-failing phenotypes. Overall, our results implicate PGC-1α and ERRα in the pathophysiology of human heart failure, and define dynamic target gene sets sharing known interrelated regulatory mechanisms capable of contributing to the mitochondrial dysfunction characteristic of this disease process.

Cardiac nuclear receptors: architects of mitochondrial structure and function

“…Indeed, Ppargc1a/b-knockout mice have reduced cardiolipin and impaired mitochondrial respiration. Third, a number of studies in animal models and in humans have shown reduced levels of PGC-1α and ERR transcripts and protein levels in heart failure (117)(118)(119)(120)(121). Collectively, these data clearly connect diminished mitochondrial respiration capacity with reduced ERR/PGC-1 signaling and suggest that this may be a final common pathway in heart failure ( Figure 3).…”

A Role for Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1) in the Regulation of Cardiac Mitochondrial Phospholipid Biosynthesis

“…The PGC-1 coactivators have also been implicated in human disease. For example, the expression and activity of PGC-1␣ has been shown to be reduced in heart failure and diabetes (15,16).…”

The Role of Altered Lipid Metabolism in Septic Myocardial Dysfunction

“…In samples taken from explanted hearts, during transplantation in patients with advanced heart failure, the level of the enzymes of FAO was low compared to the non-failing hearts [218]. The reduction of mitochondrial biogenesis and of FFA oxidation in the advanced phase of CHF is, as already seen, caused by the reactivation of the fetal gene program through the upregulation of HIF-1 and the downregulation of PPAR, \ERR, of SIRT1 and of the PGC-1network demonstrated in myocardial samples of patients with end-stage heart failure compared with explanted non failing hearts [219]. The expression of these transcription factors and coactivators is reduced in pathological hypertrophy and heart failure whereas it is upregulated in physiological forms of hypertrophy related to postnatal growth or exercise training [220] so furnishing a precise boundary between physiologic and pathologic cardiac growth.…”