PPARα-Sirt1 Complex Mediates Cardiac Hypertrophy and Failure through Suppression of the ERR Transcriptional Pathway

Abstract

SUMMARY High energy production in mitochondria is essential for maintaining cardiac contraction in the heart. Genes regulating mitochondrial function are commonly downregulated during heart failure. Here we show that both PPARα and Sirt1 are upregulated by pressure overload in the heart. Haploinsufficiency of either PPARα or Sirt1 attenuated pressure overload-induced cardiac hypertrophy and failure, whereas simultaneous upregulation of PPARα and Sirt1 exacerbated the cardiac dysfunction. PPARα and Sirt1 coordinately suppressed genes involved in mitochondrial function that are regulated by estrogen related receptors (ERRs). PPARα bound and recruited Sirt1 to the ERR response element (ERRE), thereby suppressing ERR target genes in an RXR-independent manner. Downregulation of ERR target genes was also observed during fasting, and this appeared to be an adaptive response of the heart. These results suggest that suppression of the ERR transcriptional pathway by PPARα/Sirt1, a physiological fasting response, is involved in the progression of heart failure by promoting mitochondrial dysfunction.

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…Additionally, differential expression of Sirt1 and PPARγ has been noted in Aβ-treated glia, which would fit the above-mentioned antagonistic regulation of Sirt1 by PPARγ; it has been proposed to mediate the neuroprotective reaction of astrocytes elicited by in vitro Aβ treatment [4]. Outside the brain, PPARα is one of the effectors of SIRT1's cardioprotective actions [159], although in some circumstances the SIRT1-PPARα interaction may actually promote heart hypertrophy [149].…”

Calorie restriction and sirtuins revisited

“…SIRT1 can also protect against hypertrophy at moderate levels of cardiac-specific overexpression but appears to be deleterious at higher levels (Alcendor et al 2007). Protection against hypertrophy may involve a pathway including PPARa and fat oxidation (Planavila et al 2011), although, surprisingly, one study showed that haploinsufficiency of SIRT1 or PPARa protected against hypertrophy induced by pressure overload (Oka et al 2011). Most interestingly, CR was shown to induce nuclear localization of SIRT1 in a mechanism requiring eNOS, and this was associated with increased ischemic tolerance (Shinmura et al 2008).…”

Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure

“…Mild overexpression of SIRT1 in the heart protects oxidative stress-induced cardiac ageing and retards age-dependent cardiac dysfunction, while high levels of SIRT1 expression induces oxidative stress and cardiomyopathy [22]. In addition, SIRT1 has the characteristics of prevention of cardiac hypertrophy [22,23], but it was also shown to promote cardiac hypertrophy and heart failure together with PPAR [24]. Furthermore, SIRT1 participates essentially in protecting hearts from ischemia-reperfusion injury [2527].…”