Fig. 3.

PO-induced feedback loop in the heart in association with PPARα regulation, redox balance, and energetics. The elevation of cellular NAD⁺ during PO-induced heart failure (HF) enhances the activity of Sirt1 (i.e., histone deacetylation), which targets a subset of PPARα target genes by interacting with PPARα during PO, presumably through epigenetic/transcriptional modifications. The downregulation of a subset of PPARα targets in the TCA cycle and ETC aggravates the impaired mitochondrial energetics in the PO heart, which further causes a redox imbalance. One possible therapeutic strategy targeting metabolism is to disrupt this negative feedback loop.