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Role of the ubiquitin-proteasome system in cardiac dysfunction of adipose triglyceride lipase-deficient mice.

Mussbacher M, Stessel H, Wölkart G, Haemmerle G, Zechner R, Mayer B, Schrammel A - J. Mol. Cell. Cardiol. (2014)

Bottom Line: Dysfunction of the UPS was accompanied by activation of NF-κB signaling.Chronic treatment of ATGL-deficient mice with the PPARα agonist Wy14,643 improved proteasomal function, prevented NF-κB activation and decreased oxidative stress.In summary, our data point to a hitherto unrecognized link between proteasomal function, PPARα signaling and cardiovascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, A-8010 Graz, Austria. Electronic address: marion.mussbacher@uni-graz.at.

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Feeding of WT and AKO mice with the PPARα agonist Wy14,643. Protein and mRNA expression was measured in cardiac homogenates prepared from Wy14,643-treated WT (striped bars) and AKO (gray bars) mice and compared to that of non-treated WT (open bars) and AKO (solid bars) controls. Improvement of PPARα signaling by Wy14,643 treatment was confirmed by reversal of (A) PGC-1α and (B) Tfam mRNA expression. Feeding of AKO mice with Wy14,643 reduced cardiac expression of (C, D) ubiquitinated proteins to WT levels. Protein expression of (E) NF-κB and (F) p-NF-κB but not (G) IκB was reversed in Wy14,643-treated AKO mice. Cardiac mRNA levels of the NF-κB target genes (H) TNFα and (I) MCP-1 were reduced to WT levels while increased expression of (J) HO-1 persisted after Wy14,643 treatment. Data represent mean values ± S.E.M. of 5–6 individual experiments. *p < 0.05 vs WT; #p < 0.05 vs AKO.
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f0015: Feeding of WT and AKO mice with the PPARα agonist Wy14,643. Protein and mRNA expression was measured in cardiac homogenates prepared from Wy14,643-treated WT (striped bars) and AKO (gray bars) mice and compared to that of non-treated WT (open bars) and AKO (solid bars) controls. Improvement of PPARα signaling by Wy14,643 treatment was confirmed by reversal of (A) PGC-1α and (B) Tfam mRNA expression. Feeding of AKO mice with Wy14,643 reduced cardiac expression of (C, D) ubiquitinated proteins to WT levels. Protein expression of (E) NF-κB and (F) p-NF-κB but not (G) IκB was reversed in Wy14,643-treated AKO mice. Cardiac mRNA levels of the NF-κB target genes (H) TNFα and (I) MCP-1 were reduced to WT levels while increased expression of (J) HO-1 persisted after Wy14,643 treatment. Data represent mean values ± S.E.M. of 5–6 individual experiments. *p < 0.05 vs WT; #p < 0.05 vs AKO.

Mentions: Since chronic treatment of AKO mice with PPARα agonists has been described to substantially improve cardiac performance in prior studies [9,12], we investigated whether the drug has a similar effect on cardiac proteasomal function. For this purpose, 6-week-old WT and AKO mice were fed a chow containing 0.1% Wy14,643 according to a well-established protocol [9]. To evaluate the outcome of the treatment, cardiac mRNA expression of PPARα coactivator PGC-1α (Fig. 3A) and mitochondrial transcription factor A (Tfam; Fig. 3B) was analyzed. Both, PGC-1α and Tfam mRNA were significantly decreased in ATGL-deficient hearts (Figs. 3A and B) by 52 ± 16% and 30 ± 4%, respectively. Chronic treatment with the PPARα agonist Wy14,643 restored PGC-1α and Tfam mRNA levels in AKO animals to WT niveau. These results are in good accordance with that reported by Haemmerle and colleagues [9]. As shown in Figs. 3C and D, feeding of AKO mice with the PPARα agonist reduced cardiac protein expression of ubiquitinated proteins to WT levels suggesting restored function of the UPS in those hearts. To investigate whether the observed effect was linked to altered NF-κB activation we analyzed protein expression and phosphorylation status of NF-κB RelA/p65. As illustrated in Figs. 3E and F, both parameters were reduced to WT levels upon Wy14,643 treatment. In contrast, cardiac IκB protein expression was not normalized upon feeding mice with the PPARα agonist (Fig. 3G). Furthermore, we observed that mRNA expression of inflammatory markers TNFα (Fig. 3H) and MCP-1 (Fig. 3I) were reduced to WT levels while increased expression of protective HO-1 persisted after Wy14,643 treatment (Fig. 3J).


Role of the ubiquitin-proteasome system in cardiac dysfunction of adipose triglyceride lipase-deficient mice.

Mussbacher M, Stessel H, Wölkart G, Haemmerle G, Zechner R, Mayer B, Schrammel A - J. Mol. Cell. Cardiol. (2014)

Feeding of WT and AKO mice with the PPARα agonist Wy14,643. Protein and mRNA expression was measured in cardiac homogenates prepared from Wy14,643-treated WT (striped bars) and AKO (gray bars) mice and compared to that of non-treated WT (open bars) and AKO (solid bars) controls. Improvement of PPARα signaling by Wy14,643 treatment was confirmed by reversal of (A) PGC-1α and (B) Tfam mRNA expression. Feeding of AKO mice with Wy14,643 reduced cardiac expression of (C, D) ubiquitinated proteins to WT levels. Protein expression of (E) NF-κB and (F) p-NF-κB but not (G) IκB was reversed in Wy14,643-treated AKO mice. Cardiac mRNA levels of the NF-κB target genes (H) TNFα and (I) MCP-1 were reduced to WT levels while increased expression of (J) HO-1 persisted after Wy14,643 treatment. Data represent mean values ± S.E.M. of 5–6 individual experiments. *p < 0.05 vs WT; #p < 0.05 vs AKO.
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Related In: Results  -  Collection

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f0015: Feeding of WT and AKO mice with the PPARα agonist Wy14,643. Protein and mRNA expression was measured in cardiac homogenates prepared from Wy14,643-treated WT (striped bars) and AKO (gray bars) mice and compared to that of non-treated WT (open bars) and AKO (solid bars) controls. Improvement of PPARα signaling by Wy14,643 treatment was confirmed by reversal of (A) PGC-1α and (B) Tfam mRNA expression. Feeding of AKO mice with Wy14,643 reduced cardiac expression of (C, D) ubiquitinated proteins to WT levels. Protein expression of (E) NF-κB and (F) p-NF-κB but not (G) IκB was reversed in Wy14,643-treated AKO mice. Cardiac mRNA levels of the NF-κB target genes (H) TNFα and (I) MCP-1 were reduced to WT levels while increased expression of (J) HO-1 persisted after Wy14,643 treatment. Data represent mean values ± S.E.M. of 5–6 individual experiments. *p < 0.05 vs WT; #p < 0.05 vs AKO.
Mentions: Since chronic treatment of AKO mice with PPARα agonists has been described to substantially improve cardiac performance in prior studies [9,12], we investigated whether the drug has a similar effect on cardiac proteasomal function. For this purpose, 6-week-old WT and AKO mice were fed a chow containing 0.1% Wy14,643 according to a well-established protocol [9]. To evaluate the outcome of the treatment, cardiac mRNA expression of PPARα coactivator PGC-1α (Fig. 3A) and mitochondrial transcription factor A (Tfam; Fig. 3B) was analyzed. Both, PGC-1α and Tfam mRNA were significantly decreased in ATGL-deficient hearts (Figs. 3A and B) by 52 ± 16% and 30 ± 4%, respectively. Chronic treatment with the PPARα agonist Wy14,643 restored PGC-1α and Tfam mRNA levels in AKO animals to WT niveau. These results are in good accordance with that reported by Haemmerle and colleagues [9]. As shown in Figs. 3C and D, feeding of AKO mice with the PPARα agonist reduced cardiac protein expression of ubiquitinated proteins to WT levels suggesting restored function of the UPS in those hearts. To investigate whether the observed effect was linked to altered NF-κB activation we analyzed protein expression and phosphorylation status of NF-κB RelA/p65. As illustrated in Figs. 3E and F, both parameters were reduced to WT levels upon Wy14,643 treatment. In contrast, cardiac IκB protein expression was not normalized upon feeding mice with the PPARα agonist (Fig. 3G). Furthermore, we observed that mRNA expression of inflammatory markers TNFα (Fig. 3H) and MCP-1 (Fig. 3I) were reduced to WT levels while increased expression of protective HO-1 persisted after Wy14,643 treatment (Fig. 3J).

Bottom Line: Dysfunction of the UPS was accompanied by activation of NF-κB signaling.Chronic treatment of ATGL-deficient mice with the PPARα agonist Wy14,643 improved proteasomal function, prevented NF-κB activation and decreased oxidative stress.In summary, our data point to a hitherto unrecognized link between proteasomal function, PPARα signaling and cardiovascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, A-8010 Graz, Austria. Electronic address: marion.mussbacher@uni-graz.at.

Show MeSH
Related in: MedlinePlus