<i>Pparα</i> and <i>Pparγ</i> expressions in visceral adipose and aortic tissues of PPAR agonist-treated DKO mice.

<p>Data are means ± SEM.</p>*<p><i>P<</i>0.05 and</p>***<p><i>P<</i>0.001 DKO compared with C57BL/6 J mice;</p>$$<p><i>P</i><0.01 and</p>$$$<p><i>P</i><0.001 PPAR agonist-treated compared with placebo-treated DKO mice;</p>£<p><i>P</i><0.05 and</p>£££<p><i>P</i><0.001 rosiglitazone-treated compared with fenofibrate-treated DKO mice.</p

HFD increases atherogenesis in insulin resistant mice.

<p>Plaque volume was determined by measuring lipid (oil red O)-stained surfaces in subsequent sections; macrophages were stained with anti-Mac-3 antibody. Gene expression in the aorta was analyzed by measuring relative <i>RNA</i> levels using qRT-PCR for <i>Pparγ</i>, <i>Mcp1, Irak3</i> and <i>Adipoq</i>. Data are means ± SEM. **<i>P</i><0.01 and ***<i>P</i><0.001 HFD-fed compared with SD-fed LDL-receptor deficient mice. Abbreviations: HFD, high fat diet; SD, standard diet.</p

Adiponectin-induced Irak3 plays an important role in rosiglitazone-mediated decrease of Mcp1.

<p>(<b>A</b>) Soluble Mcp1 protein levels in DKO BMDM exposed to 50 µM fenofibrate, 10 µM rosiglitazone or 5 µM GW9662 for 24 hours as determined by ELISA. Data are means ± SEM; n = 16 from three different mice. ^{P<0.01 compared with fenofibrate-treated BMDM. (B) Irak3 RNA and protein levels of DKO BMDM exposed to 1 or 10 µg/mL globular adiponectin for 24 hours as determined by qRT-PCR and Western blotting. Data are means ± SEM; n = 6. ***P<0.001 compared with DKO BMDM; ^$P<0.05 and}<i>P</i><0.01 compared with DKO BMDM exposed to 1 µg/mL globular adiponectin. (<b>C</b>) Soluble Mcp1 protein levels (n = 18 from three different mice), NFκB p50 DNA binding activity (n = 8 from two different mice) and mROS production (n = 6) in IRAK3^−/− BMDM exposed to 50 µM fenofibrate or 10 µM rosiglitazone for 24 hours as determined by ELISA and flow cytometry. Data are means ± SEM. *<i>P</i><0.05, **<i>P</i><0.01 and ***<i>P</i><0.001 compared with C57BL/6 J BMDM; ^$<i>P</i><0.05 and ^$$$<i>P</i><0.001 compared with IRAK3^−/− BMDM; ^£££<i>P</i><0.001 compared with fenofibrate-treated BMDM. Abbreviations: BMDM, bone marrow-derived macrophages; mROS, mitochondrial reactive oxygen species.</p

Adiponectin and macrophage-associated Irak3 are indispensable molecules in the anti-atherosclerotic properties of PPAR agonists.

<p>The schematic draw demonstrates the anti-atherosclerotic properties of the PPARγ agonist rosiglitazone. Treatment with rosiglitazone improves the adipocyte function characterized by a decrease in adipocyte size, a reduction in adipose tissue macrophages and an increased expression of anti-inflammatory adiponectin. The increase in blood adiponectin and <i>de novo</i> adiponectin production in atherosclerotic lesions is necessary for the upregulation of Irak3 in plaque macrophages, which is crucial for the indirect rosiglitazone-mediated decrease in Mcp1 secretion. Abbreviations: Mφ, macrophages; ROS, reactive oxygen species.</p

Rosiglitazone and not fenofibrate treatment decreases atherogenesis in obese, insulin resistant mice.

<p>(<b>A</b>) Representative Mac-3 staining of aortic sinus plaques of placebo-, fenofibrate- and rosiglitazone-treated DKO mice at 24 weeks. (<b>B</b>) Gene expression in the aorta was analyzed by measuring relative <i>RNA</i> levels using qRT-PCR for <i>Tnfα</i>, <i>IL6</i>, <i>Mcp1</i> and <i>Irak3</i>. Data are means ± SEM. Scale bar = 500 µm. *<i>P</i><0.05, **<i>P</i><0.01 and ***<i>P</i><0.001 DKO compared with C57BL/6 J mice; ^$$<i>P</i><0.01 and ^$$$<i>P</i><0.001 PPAR agonist-treated compared with placebo-treated DKO mice; ^£<i>P</i><0.05, ^££<i>P</i><0.01 and ^£££<i>P</i><0.001 rosiglitazone-treated compared with fenofibrate-treated DKO mice.</p

HFD-induced weight gain is associated with dyslipidemia, insulin resistance and hyperleptinemia in the presence of high blood adiponectin.

<p>Data are means ± SEM. **<i>P</i><0.01 and ***<i>P</i><0.001 HFD-fed compared with SD-fed LDL-receptor deficient mice. Abbreviations: HFD, high fat diet; SD, standard diet.</p

Blood, adipose tissue and plaque variables.

<p>Data are means ± SEM.</p>*<p><i>P<</i>0.05,</p>**<p><i>P<</i>0.01 and</p>***<p><i>P<</i>0.001 DKO compared with C57BL/6 J mice;</p>$<p><i>P</i><0.05,</p>$$<p><i>P</i><0.01 and</p>$$$<p><i>P</i><0.001 PPAR agonist-treated compared with placebo-treated DKO mice;</p>£<p><i>P</i><0.05,</p>££<p><i>P</i><0.01 and</p>£££<p><i>P</i><0.001 rosiglitazone-treated compared with fenofibrate-treated DKO mice.</p><p>Abbreviations: CLS, crown-like structures; ND, not detectable.</p

Low Cytochrome Oxidase 1 Links Mitochondrial Dysfunction to Atherosclerosis in Mice and Pigs

<div><p>Background</p><p>Cytochrome oxidase IV complex regulates energy production in mitochondria. Therefore, we determined the relation of COX genes with atherosclerosis in mice and pigs.</p><p>Methods and results</p><p>First, we compared atherosclerosis in the aortic arch of age-matched (24 weeks) C57BL/6J control (n = 10), LDL-receptor deficient (n = 8), leptin-deficient ob/ob (n = 10), and double knock-out (lacking LDL-receptor and leptin) mice (n = 12). Low aortic <i>mitochondria-encoded cytochrome oxidase 1</i> in obese diabetic double knock-out mice was associated with a larger plaque area and higher propensity of M1 macrophages and oxidized LDL. Caloric restriction increased <i>mitochondria-encoded cytochrome oxidase 1</i> and reduced plaque area and oxidized LDL. This was associated with a reduction of titer of anti-oxidized LDL antibodies, a proxy of systemic oxidative stress. Low of <i>mitochondria-encoded cytochrome oxidase 1</i> was related to low expression of peroxisome proliferative activated receptors α, δ, and γ and of peroxisome proliferative activated receptor, gamma, co-activator 1 alpha reflecting mitochondrial dysfunction. Caloric restriction increased them. To investigate if there was a diabetic/obesity requirement for <i>mitochondria-encoded cytochrome oxidase 1</i> to be down-regulated, we then studied atherosclerosis in LAD of hypercholesterolemic pigs (n = 37). Pigs at the end of the study were divided in three groups based on increasing LAD plaque complexity according to Stary (Stary I: n = 12; Stary II: n = 13; Stary III: n = 12). Low <i>mitochondria-encoded cytochrome oxidase 1</i> in isolated plaque macrophages was associated with more complex coronary plaques and oxidized LDL. Nucleus-encoded cytochrome oxidase <i>4I1</i> and cytochrome oxidase <i>10</i> did not correlate with plaque complexity and oxidative stress. In mice and pigs, <i>MT-COI</i> was inversely related to insulin resistance.</p><p>Conclusions</p><p>Low <i>MT-COI</i> is related to mitochondrial dysfunction, oxidative stress and atherosclerosis and plaque complexity.</p></div

Inhibition of ppTG in the plasma at four hours following the olive oil gavage following administration of 50 mg/kg of active (AP5055, AP5258) or inactive (AP5156) analogues.

<p>Inhibition of ppTG in the plasma at four hours following the olive oil gavage following administration of 50 mg/kg of active (AP5055, AP5258) or inactive (AP5156) analogues.</p

Reduction of plasma triglycerides.

<p>Comparative effect of CD36 inhibitors on the plasma concentrations of TG in different rat models, A: Dose dependent reduction in a fructose fed rat, AP5055 was administrated at different doses for 3 w (n = 12), B: AP5258 was administrated to diabetic ZDF rats (C = Control, T = Treated) for a period of 2w at 10 mg/kg (n = 8).</p