Inhibition of Lipoprotein-Associated Phospholipase A2 Ameliorates Inflammation and Decreases Atherosclerotic Plaque Formation in ApoE-Deficient Mice

Abstract Background Fibroblast activation protein (FAP) is a serine protease that is upregulated in sites of tissue remodeling, including arthritis, tumors and atherosclerosis. We have reported that FAP degrades type I collagen in human thin-cap fibroatheromata; its expression is enhanced in advanced human plaques and induced by inflammation. However, the role of endogenous FAP in atherosclerosis remains unknown. Purpose To investigate the effects of constitutive Fap loss-of-function on atherosclerotic plaque formation and vulnerability. Methods and results Male 8-week-old Apoe−/− Fap+/+ and Apoe−/− Fap−/− mice were fed a high-cholesterol diet (1.25% chol) for 12 weeks. En face analyses of thoracoabdominal aortae using Oil Red O (ORO) revealed decreased plaques in Apoe−/− Fap−/− mice (5.7±0.5%; n=21) compared to Apoe−/− Fap+/+ mice (10.7±0.7%; n=24; p<0.0001). In parallel, ORO analyses of serial aortic root cross sections showed diminished plaques in Fap-deficient mice (18.4±3.4% vs 27.6±2.1%). As a surrogate of plaque vulnerability, fibrous cap thickness was increased in Apoe−/− Fap−/− mice (65±6 mm vs 35±3 mm; p<0.01), whereas necrotic core size, plaque macrophages (CD68) and T cells (CD3) accumulation, as well as VCAM1 expression did not differ. These changes were independent of plasma triglycerides, total and LDL-cholesterol levels. Plasma of Fap-deficient mice showed decreased FAP activity compared to Fap wildtype controls. Notably, second harmonics generation in cross sections of aortic root plaques showed that the deposition and density of fibrillar collagens was enhanced in Fap-deficient (25.5±4.4%) compared to control plaques (13.8±2.5%; p<0.05). Consistently, Fap deletion led to an accumulation of uncleaved pre-COL3A1, a proteolytic target of FAP. Conclusions Constitutive Fap deletion decreases experimental atherosclerosis and features of plaque vulnerability. Thus, inhibition of FAP expression or activity may be a promising therapeutic target in atherosclerosis. Acknowledgement/Funding Swiss National Science Foundation, Swiss Heart Foundation

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P3785Deletion of cyclophilin d inhibits atherosclerotic plaque formation in apolipoprotein-e deficient mice

European Heart Journal ◽

10.1093/eurheartj/ehy563.p3785 ◽

2018 ◽

Vol 39 (suppl_1) ◽

Author(s):

R Umezu ◽

J Koga ◽

H Tsutsui ◽

K Egashira

Keyword(s):

Apolipoprotein E ◽

Atherosclerotic Plaque ◽

Plaque Formation ◽

Cyclophilin D ◽

Atherosclerotic Plaque Formation ◽

Deficient Mice

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Neprilysin Inhibitor–Angiotensin II Receptor Blocker Combination Therapy (Sacubitril/valsartan) Suppresses Atherosclerotic Plaque Formation and Inhibits Inflammation in Apolipoprotein E- Deficient Mice

Scientific Reports ◽

10.1038/s41598-019-42994-1 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 7

Author(s):

Hui Zhang ◽

Gangqiong Liu ◽

Wenping Zhou ◽

Wenjing Zhang ◽

Kai Wang ◽

...

Keyword(s):

Angiotensin Ii ◽

Combination Therapy ◽

Apolipoprotein E ◽

Atherosclerotic Plaque ◽

Plaque Formation ◽

Angiotensin Ii Receptor Blocker ◽

Angiotensin Ii Receptor ◽

Neprilysin Inhibitor ◽

Atherosclerotic Plaque Formation ◽

Deficient Mice

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CXCR3 Antagonist NBI-74330 Attenuates Atherosclerotic Plaque Formation in LDL Receptor–Deficient Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.107.147827 ◽

2008 ◽

Vol 28 (2) ◽

pp. 251-257 ◽

Cited By ~ 70

Author(s):

Eva J.A. van Wanrooij ◽

Saskia C.A. de Jager ◽

Thomas van Es ◽

Paula de Vos ◽

Helen L. Birch ◽

...

Keyword(s):

Atherosclerotic Plaque ◽

Ldl Receptor ◽

Plaque Formation ◽

Atherosclerotic Plaque Formation ◽

Deficient Mice

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Inulin attenuates atherosclerosis in apolipoprotein E-deficient mice

British Journal Of Nutrition ◽

10.1017/bjn20061913 ◽

2006 ◽

Vol 96 (5) ◽

pp. 840-844 ◽

Cited By ~ 51

Author(s):

Marie-Hélène Rault-Nania ◽

Elyett Gueux ◽

Céline Demougeot ◽

Christian Demigné ◽

Edmond Rock ◽

...

Keyword(s):

Atherosclerotic Plaque ◽

Plasma Cholesterol ◽

Control Diet ◽

Atherosclerotic Lesion ◽

Plaque Formation ◽

Control Group ◽

Apo E ◽

Atherosclerotic Plaque Formation ◽

Deficient Mice ◽

Long Chain

Effects of different inulin-type fructan fractions were studied on atherosclerotic plaque formation in male apo E-deficient mice. Thirty-two mice were randomly divided into four groups and received either a semi-purified sucrose-based diet (control group), or diets in which sucrose was replaced in part by various inulin-type fructans (10 g/100 g): long-chain inulin, oligofructose, or an oligofructose-enriched inulin for 16 weeks. The presence of atherosclerotic plaques was assessed by histomorphometry in the aortic sinus. The apo E-deficient mice fed long-chain inulin or an oligofructose-enriched inulin had about 35 % and 25 % less atherosclerotic lesion area compared with the control group, respectively. Feeding long-chain inulin significantly reduced plasma cholesterol concentrations (P<0·001), and the three inulin-type fructans reduced triacylglycerol (TAG) concentrations compared with the control group (P<0·001). Both the long-chain inulin and an oligofructose-enriched inulin significantly lowered hepatic cholesterol concentrations compared with the control diet (P<0·05). Hepatic TAG concentrations were significantly lower in all three groups fed the fructan-supplemented diets v. the control group (P<0·0001). The results of the present study suggest that inhibition of atherosclerotic plaque formation is more potent in the presence of long-chain inulin, either alone or in combination with oligofructose (an oligofructose-enriched inulin), and that this probably is related to changes in lipid metabolism.

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Abstract 18661: Regulation of Lymphatic Physiology by Connexin47

Circulation ◽

10.1161/circ.132.suppl_3.18661 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Merlijn J Meens ◽

Issa Kutkut ◽

Amélie Sabine ◽

Tatiana V Petrova ◽

Brenda R Kwak

Keyword(s):

Atherosclerotic Plaque ◽

Lymphatic Drainage ◽

Plaque Formation ◽

Lymphatic Endothelial Cells ◽

Lipid Levels ◽

Plaque Development ◽

Atherosclerotic Plaque Formation ◽

Aortic Plaques ◽

Old Mice ◽

Deficient Mice

Introduction: Mutations in GJC2, which encodes connexin47 (Cx47), are associated with lymphedema. Moreover, Cx47 mRNA was recently found in human lymphatic endothelial cells (LECs). Hypothesis: Lymphatic endothelial Cx47 has a role in lymphatic physiology and pathology. Methods: Confocal microscopy and qPCRs were used to assess expression of Cx47. Lymphatic drainage was studied by subcutaneous Evans Blue injections in the footpad of 12 week-old ApoE -/- or Cx47 eGFP/eGFP ApoE -/- mice. Atherosclerosis was studied in 15 months-old ApoE -/- or Cx47 eGFP/eGFP ApoE -/- mice. Results: Cx47 was expressed in lymphangions of mesenteric collecting vessels in Cx47 eGFP/eGFP Prox1-mOrange2 mice as assessed by microscopy and its expression was confirmed by qPCR on mesentery, gut and skin mRNA of ApoE -/- but not Cx47 eGFP/eGFP ApoE -/- mice. Interestingly, lymphatic drainage was enhanced in Cx47-deficient mice (n=10/11, p<0.05). To address whether Cx47 affects chronic immuno-inflammatory pathology atherosclerotic plaque formation was studied in 15-month old male ApoE -/- and Cx47 eGFP/eGFP ApoE -/- mice on regular chow. These studies showed that Cx47-deficiency does not affect the size or composition (e.g. lipid, collagen or macrophage content) of aortic plaques in the aortic root. However, plaque development in the thoracic-abdominal aorta of 15 months-old mice tended to be larger in Cx47 eGFP/eGFP ApoE -/- mice (21±5 vs 30±4 % lipid area, n=10, p=0.08). Unexpectedly, total cholesterol (TC) and LDL, but not HDL, triglycerides or free fatty acids, were increased in serum of Cx47 eGFP/eGFP ApoE -/- mice as compared to ApoE -/- serum (TC: 472±24 vs 647±18 mg/dL, n=10, p<0.01; and LDL: 272±20 vs 443±17 mg/dL, n=10, p<0.001, respectively). Increased lymphatic drainage from plaques in Cx47 eGFP/eGFP ApoE -/- mice may, partially, compensate for increased serum TC and LDL thereby preventing exuberant atherosclerotic plaque formation despite increased serum lipid levels. Conclusions: In conclusion, Cx47 is expressed in LECs of the lymphangion and seems implicated in multiple aspects of lymphatic (patho)physiology.

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