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Peroxisome Proliferator Activated Receptor-? Association With Silent Information Regulator 1 Suppresses Cardiac Fatty Acid Metabolism in the Failing Heart.

ABSTRACT: Heart failure is accompanied by changes in cardiac metabolism characterized by reduced fatty acid (FA) utilization. However, the underlying mechanism and its causative involvement in the progression of heart failure are poorly understood. The peroxisome proliferator activated receptor-? (PPAR?)/retinoid X receptor (RXR) heterodimer promotes transcription of genes involved in FA metabolism through binding to the PPAR response element, called direct repeat 1 (DR1). Silent information regulator 1 (Sirt1) is a histone deacetylase, which interacts with PPAR?.To investigate the role of PPAR? in the impaired FA utilization observed during heart failure, genetically altered mice were subjected to pressure overload. The DNA binding of PPAR?, RXR?, and Sirt1 to DR1 was evaluated with oligonucleotide pull-down and chromatin immunoprecipitation assays. Although the binding of PPAR? to DR1 was enhanced in response to pressure overload, that of RXR? was attenuated. Sirt1 competes with RXR? to dimerize with PPAR?, thereby suppressing FA utilization in the failing heart. DR1 sequence analysis indicated that the typical DR1 sequence favors PPAR?/RXR? heterodimerization, whereas the switch from RXR? to Sirt1 takes place on degenerate DR1s. Sirt1 bound to PPAR? through a region homologous to the PPAR? binding domain in RXR?. A short peptide corresponding to the RXR? domain not only inhibited the interaction between PPAR? and Sirt1 but also improved FA metabolism and ameliorated cardiac dysfunction.A change in the heterodimeric partner of PPAR? from RXR? to Sirt1 is responsible for the impaired FA metabolism and cardiac dysfunction in the failing heart.

SUBMITTER: Oka S

PROVIDER: S-EPMC4651813 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Peroxisome Proliferator Activated Receptor-α Association With Silent Information Regulator 1 Suppresses Cardiac Fatty Acid Metabolism in the Failing Heart.

Oka Shin-ichi S Zhai Peiyong P Yamamoto Takanobu T Ikeda Yoshiyuki Y Byun Jaemin J Hsu Chiao-Po CP Sadoshima Junichi J

Circulation. Heart failure 20151006 6

<h4>Background</h4>Heart failure is accompanied by changes in cardiac metabolism characterized by reduced fatty acid (FA) utilization. However, the underlying mechanism and its causative involvement in the progression of heart failure are poorly understood. The peroxisome proliferator activated receptor-α (PPARα)/retinoid X receptor (RXR) heterodimer promotes transcription of genes involved in FA metabolism through binding to the PPAR response element, called direct repeat 1 (DR1). Silent inform ...[more]

PMID: 26443578

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Project description:BackgroundSkeletal muscle regeneration is an adaptive response to injury that is crucial to the maintenance of muscle mass and function. A p21-activated kinase 4 (PAK4) serine/threonine kinase is critical to the regulation of cytoskeletal changes, cell proliferation, and growth. However, PAK4's role in myoblast differentiation and regenerative myogenesis remains to be determined.MethodsWe used a mouse model of myotoxin (notexin)-induced muscle regeneration. In vitro myogenesis was performed in the C2C12 myoblast cell line, primary myoblasts, and primary satellite cells. In vivo overexpression of PAK4 or kinase-inactive mutant PAK4S474A was conducted in skeletal muscle to examine PAK4's kinase-dependent effect on muscle regeneration. The regeneration process was evaluated by determining the number and size of multinucleated myofibres and expression patterns of myogenin and eMyHC. To explore whether PAK4 inhibition improves muscle regeneration, mice were injected intramuscularly with siRNA that targeted PAK4 or orally administered with a chemical inhibitor of PAK4.Resultsp21-activated kinase 4 was highly expressed during the myoblast stage, but expression gradually and substantially decreased as myoblasts differentiated into myotubes. PAK4 overexpression, but not kinase-inactive mutant PAK4S474A overexpression, significantly impeded myoblast fusion and MyHC-positive myotube formation in C2C12 cells, primary myoblasts, and satellite cells (P < 0.01). Conversely, PAK4 silencing led to an 8.7% and a 20.3% increase in the number of multinucleated larger myotubes in C2C12 cells and primary myoblasts. Further, in vivo overexpression of PAK4 by adenovirus injection to mice prior to and after myotoxin-induced injury led to a 52.6% decrease in the number of eMyHC-positive myofibres on Day 5 in tibialis anterior muscles as compared with those injected with control adenoviruses (P < 0.01), while Ad-PAK4S474A showed comparable muscle regeneration parameters. PAK4-induced repression of muscle regeneration coincided with an increase in phosphatase and tensin homologue (PTEN) expression and a decrease in phosphoinositide 3-kinase-Akt signalling. In contrast, PAK4 silencing reduced PTEN expression in mice. Consistent with these findings, prodrug of PAK4 inhibitor CZh-226 (30 mg/kg) orally administered to mice repressed PTEN expression and accelerated myotube formation. Subsequent mechanistic studies revealed that PAK4 directly phosphorylates PPARγ at S273 to increase its transcription activity, thereby up-regulating PTEN expression. Importantly, an analysis of the Genotype-Tissue Expression database showed a positive correlation between PAK4 and PTEN in human skeletal muscle tissues (P < 0.01).Conclusionsp1-activated kinase 4 is a new member of PPARγ kinase, and PAK4 inhibition may have a therapeutic role as an accelerant of muscle regeneration.

Dataset Information

Peroxisome Proliferator Activated Receptor-? Association With Silent Information Regulator 1 Suppresses Cardiac Fatty Acid Metabolism in the Failing Heart.

Publications

Peroxisome Proliferator Activated Receptor-α Association With Silent Information Regulator 1 Suppresses Cardiac Fatty Acid Metabolism in the Failing Heart.

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