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Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation.

ABSTRACT: Atherosclerotic lesions are asymmetric focal thickenings of the intima of arteries that consist of lipids, various cell types and extracellular matrix (ECM). These lesions lead to vascular occlusion representing the most common cause of death in the Western world. The main cause of vascular occlusion is rupture of atheromatous lesions followed by thrombus formation. Fibronectin (FN) is one of the earliest ECM proteins deposited at atherosclerosis-prone sites and was suggested to promote atherosclerotic lesion formation. Here, we report that atherosclerosis-prone apolipoprotein E-null mice lacking hepatocyte-derived plasma FN (pFN) fed with a pro-atherogenic diet display dramatically reduced FN depositions at atherosclerosis-prone areas, which results in significantly smaller and fewer atherosclerotic plaques. However, the atherosclerotic lesions from pFN-deficient mice lacked vascular smooth muscle cells and failed to develop a fibrous cap. Thus, our results demonstrate that while FN worsens the course of atherosclerosis by increasing the atherogenic plaque area, it promotes the formation of the protective fibrous cap, which in humans prevents plaques rupture and vascular occlusion.

SUBMITTER: Rohwedder I

PROVIDER: S-EPMC3407945 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation.

Rohwedder Ina I Montanez Eloi E Beckmann Karsten K Bengtsson Eva E Dunér Pontus P Nilsson Jan J Soehnlein Oliver O Fässler Reinhard R

EMBO molecular medicine 20120419 7

Atherosclerotic lesions are asymmetric focal thickenings of the intima of arteries that consist of lipids, various cell types and extracellular matrix (ECM). These lesions lead to vascular occlusion representing the most common cause of death in the Western world. The main cause of vascular occlusion is rupture of atheromatous lesions followed by thrombus formation. Fibronectin (FN) is one of the earliest ECM proteins deposited at atherosclerosis-prone sites and was suggested to promote atherosc ...[more]

PMID: 22514136

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Project description:OBJECTIVE:Mitochondrial DNA (mtDNA) damage is present in murine and human atherosclerotic plaques. However, whether endogenous levels of mtDNA damage are sufficient to cause mitochondrial dysfunction and whether decreasing mtDNA damage and improving mitochondrial respiration affects plaque burden or composition are unclear. We examined mitochondrial respiration in human atherosclerotic plaques and whether augmenting mitochondrial respiration affects atherogenesis. APPROACH AND RESULTS:Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E-deficient (ApoE-/-) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE-/- mice overexpressing the mitochondrial helicase Twinkle (Tw+/ApoE-/-). Tw+/ApoE-/- mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw+/ApoE-/- mice had decreased necrotic core and increased fibrous cap areas, and Tw+/ApoE-/- bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress-induced apoptosis. CONCLUSIONS:Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen species and may be a promising therapeutic strategy in atherosclerosis.

Project description:Background Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and leukocytes within the arterial wall. By investigating the aortic transcriptome of atherosclerosis prone apolipoprotein E (ApoE-/-) mice, we aimed to identify new players in the development and progression of atherosclerosis. Methods RNA-Seq from aorta ApoE-/- mice was compared to healthy aorta. AnxA8 expression was assessed in human and mice atherosclerotic tissue and healthy aorta. ApoE-/- mice lacking systemic AnxA8 (ApoE-/-AnxA8-/-) were generated to assess the functional role of AnxA8. Bone marrow transplantation (BMT) was also done to generate ApoE-/- lacking AnxA8 specifically in bone marrow-derived cells. Intravital microscopy was used to analyze platelets and leukocyte adhesion in atheroprone mice. The role of AnxA8 was analyzed in cultured endothelial cells. Results RNA-Seq unveiled AnxA8 as one of the most significantly up-regulated genes in atherosclerotic aorta of ApoE-/- mice compared with wild type. Moreover, AnxA8 was also upregulated in human atherosclerotic plaques. Germline deletion of AnxA8 decreased atherosclerotic burden and atherosclerotic plaques size and volume in the aortic root. Plaques of ApoE-/-AnxA8-/- were characterized by a less lipid and inflammatory content compared with those in ApoE-/-AnxA8+/+. BMT showed that hematopoietic AnxA8 deficiency had no effect on atherosclerotic development. Oxidized-LDL (ox-LDL) increased AnxA8 mRNA and protein expression in murine aortic endothelial cells (MAECs). Subsequent in vitro experiments revealed that AnxA8 deficiency in MAECs suppressed P/E-selectin and CD31 expression and secretion induced by ox-LDL with a concomitant reduction in platelets and leukocyte adhesion. Intravital microscopy confirmed the decrease in leukocyte rolling and adhesion, and platelets adhesion, in ApoE-/-AnxA8-/- mice. Conclusion Our findings demonstrate that AnxA8 deficiency decreases atherosclerosis progression through regulating leukocyte infiltration and vascular inflammation.

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Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation.

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Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation.

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