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The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression.

Miranda MX, van Tits LJ, Lohmann C, Arsiwala T, Winnik S, Tailleux A, Stein S, Gomes AP, Suri V, Ellis JL, Lutz TA, Hottiger MO, Sinclair DA, Auwerx J, Schoonjans K, Staels B, Lüscher TF, Matter CM - Eur. Heart J. (2014)

Bottom Line: Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects.Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation.Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.

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SRT3025 increases hepatic Ldlr protein expression while decreasing plasma Pcsk9 in Apoe−/− mice. Eight week-old Apoe−/− mice were fed a high-cholesterol diet (1.25% w/w) supplemented with the Sirt1 activator SRT3025 (n = 9) or placebo (n = 9) for 12 weeks. (A) Relative mRNA expression levels of hepatic genes involved in cholesterol regulation. (B) Western blots of liver lysates for Ldlr, Pcsk9, and β-actin. (C) Plasma levels of Pcsk9. HCD, high-cholesterol diet; Pcsk9, proprotein convertase subtilisin/kexin type 9.
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EHU095F3: SRT3025 increases hepatic Ldlr protein expression while decreasing plasma Pcsk9 in Apoe−/− mice. Eight week-old Apoe−/− mice were fed a high-cholesterol diet (1.25% w/w) supplemented with the Sirt1 activator SRT3025 (n = 9) or placebo (n = 9) for 12 weeks. (A) Relative mRNA expression levels of hepatic genes involved in cholesterol regulation. (B) Western blots of liver lysates for Ldlr, Pcsk9, and β-actin. (C) Plasma levels of Pcsk9. HCD, high-cholesterol diet; Pcsk9, proprotein convertase subtilisin/kexin type 9.

Mentions: Histomorphometry of thoraco-abdominal aortae en face and cross-sections of aortic roots revealed a significant reduction in plaque size in SRT3025-treated Apoe−/− mice compared with placebo-treated controls (Figure 1A and B). Moreover, a marked reduction of Cd68-positive macrophages within the plaque and Vcam-1 expression in aortic roots was observed (Figure 1C and D). Interestingly, plasma levels of total-, LDL- and VLDL-cholesterol were significantly lower after SRT3025 treatment compared with placebo (Figure 1E and F). Triglycerides and HDL-cholesterol remained unchanged (Supplementary material online, Figure S1A). In addition, we observed reduced plasma levels of Mcp-1 and Il-6 (Figure 1G) and lower hepatic mRNA expression of these cytokines (Figure 3A).Figure 1


The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression.

Miranda MX, van Tits LJ, Lohmann C, Arsiwala T, Winnik S, Tailleux A, Stein S, Gomes AP, Suri V, Ellis JL, Lutz TA, Hottiger MO, Sinclair DA, Auwerx J, Schoonjans K, Staels B, Lüscher TF, Matter CM - Eur. Heart J. (2014)

SRT3025 increases hepatic Ldlr protein expression while decreasing plasma Pcsk9 in Apoe−/− mice. Eight week-old Apoe−/− mice were fed a high-cholesterol diet (1.25% w/w) supplemented with the Sirt1 activator SRT3025 (n = 9) or placebo (n = 9) for 12 weeks. (A) Relative mRNA expression levels of hepatic genes involved in cholesterol regulation. (B) Western blots of liver lysates for Ldlr, Pcsk9, and β-actin. (C) Plasma levels of Pcsk9. HCD, high-cholesterol diet; Pcsk9, proprotein convertase subtilisin/kexin type 9.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4286317&req=5

EHU095F3: SRT3025 increases hepatic Ldlr protein expression while decreasing plasma Pcsk9 in Apoe−/− mice. Eight week-old Apoe−/− mice were fed a high-cholesterol diet (1.25% w/w) supplemented with the Sirt1 activator SRT3025 (n = 9) or placebo (n = 9) for 12 weeks. (A) Relative mRNA expression levels of hepatic genes involved in cholesterol regulation. (B) Western blots of liver lysates for Ldlr, Pcsk9, and β-actin. (C) Plasma levels of Pcsk9. HCD, high-cholesterol diet; Pcsk9, proprotein convertase subtilisin/kexin type 9.
Mentions: Histomorphometry of thoraco-abdominal aortae en face and cross-sections of aortic roots revealed a significant reduction in plaque size in SRT3025-treated Apoe−/− mice compared with placebo-treated controls (Figure 1A and B). Moreover, a marked reduction of Cd68-positive macrophages within the plaque and Vcam-1 expression in aortic roots was observed (Figure 1C and D). Interestingly, plasma levels of total-, LDL- and VLDL-cholesterol were significantly lower after SRT3025 treatment compared with placebo (Figure 1E and F). Triglycerides and HDL-cholesterol remained unchanged (Supplementary material online, Figure S1A). In addition, we observed reduced plasma levels of Mcp-1 and Il-6 (Figure 1G) and lower hepatic mRNA expression of these cytokines (Figure 3A).Figure 1

Bottom Line: Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects.Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation.Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.

Show MeSH
Related in: MedlinePlus