The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice
ABSTRACT Atherosclerotic plaque development depends on chronic inflammation of the arterial wall. A dysbiotic gut microbiota can cause low-grade inflammation, and microbiota composition was linked to cardiovascular disease risk. However, the role of this environmental factor in atherothrombosis rema...
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American Society for Microbiology
2019
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oai:doaj.org-article:20c67fc195d04a29b3eecc489e3dc2762021-11-15T15:59:41ZThe Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice10.1128/mBio.02298-192150-7511https://doaj.org/article/20c67fc195d04a29b3eecc489e3dc2762019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02298-19https://doaj.org/toc/2150-7511ABSTRACT Atherosclerotic plaque development depends on chronic inflammation of the arterial wall. A dysbiotic gut microbiota can cause low-grade inflammation, and microbiota composition was linked to cardiovascular disease risk. However, the role of this environmental factor in atherothrombosis remains undefined. To analyze the impact of gut microbiota on atherothrombosis, we rederived low-density lipoprotein receptor-deficient (Ldlr−/−) mice as germfree (GF) and kept these mice for 16 weeks on an atherogenic high-fat Western diet (HFD) under GF isolator conditions and under conventionally raised specific-pathogen-free conditions (CONV-R). In spite of reduced diversity of the cecal gut microbiome, caused by atherogenic HFD, GF Ldlr−/− mice and CONV-R Ldlr−/− mice exhibited atherosclerotic lesions of comparable sizes in the common carotid artery. In contrast to HFD-fed mice, showing no difference in total cholesterol levels, CONV-R Ldlr−/− mice fed control diet (CD) had significantly reduced total plasma cholesterol, very-low-density lipoprotein (VLDL), and LDL levels compared with GF Ldlr−/− mice. Myeloid cell counts in blood as well as leukocyte adhesion to the vessel wall at the common carotid artery of GF Ldlr−/− mice on HFD were diminished compared to CONV-R Ldlr−/− controls. Plasma cytokine profiling revealed reduced levels of the proinflammatory chemokines CCL7 and CXCL1 in GF Ldlr−/− mice, whereas the T-cell-related interleukin 9 (IL-9) and IL-27 were elevated. In the atherothrombosis model of ultrasound-induced rupture of the common carotid artery plaque, thrombus area was significantly reduced in GF Ldlr−/− mice relative to CONV-R Ldlr−/− mice. Ex vivo, this atherothrombotic phenotype was explained by decreased adhesion-dependent platelet activation and thrombus growth of HFD-fed GF Ldlr−/− mice on type III collagen. IMPORTANCE Our results demonstrate a functional role for the commensal microbiota in atherothrombosis. In a ferric chloride injury model of the carotid artery, GF C57BL/6J mice had increased occlusion times compared to colonized controls. Interestingly, in late atherosclerosis, HFD-fed GF Ldlr−/− mice had reduced plaque rupture-induced thrombus growth in the carotid artery and diminished ex vivo thrombus formation under arterial flow conditions.Klytaimnistra KiouptsiSven JäckelGiulia PontarolloAlexandra GrillMarijke J. E. KuijpersEivor WilmsChristian WeberFelix SommerMagdolna NagyCarlos NeideckYvonne JansenStefanie AscherHenning FormesCornelia KarwotFranziska BayerBettina KollarSaravanan SubramaniamMichael MolitorPhilip WenzelPhilip RosenstielHristo TodorovSusanne GerberUlrich WalterKerstin JurkJohan W. M. HeemskerkEmiel P. C. van der VorstYvonne DöringChristoph ReinhardtAmerican Society for Microbiologyarticlegut microbiotagermfreelow-density lipoprotein receptorarterial thrombosisatherothrombosiscarotid arteryMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019) |
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EN |
| topic |
gut microbiota germfree low-density lipoprotein receptor arterial thrombosis atherothrombosis carotid artery Microbiology QR1-502 |
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gut microbiota germfree low-density lipoprotein receptor arterial thrombosis atherothrombosis carotid artery Microbiology QR1-502 Klytaimnistra Kiouptsi Sven Jäckel Giulia Pontarollo Alexandra Grill Marijke J. E. Kuijpers Eivor Wilms Christian Weber Felix Sommer Magdolna Nagy Carlos Neideck Yvonne Jansen Stefanie Ascher Henning Formes Cornelia Karwot Franziska Bayer Bettina Kollar Saravanan Subramaniam Michael Molitor Philip Wenzel Philip Rosenstiel Hristo Todorov Susanne Gerber Ulrich Walter Kerstin Jurk Johan W. M. Heemskerk Emiel P. C. van der Vorst Yvonne Döring Christoph Reinhardt The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice |
| description |
ABSTRACT Atherosclerotic plaque development depends on chronic inflammation of the arterial wall. A dysbiotic gut microbiota can cause low-grade inflammation, and microbiota composition was linked to cardiovascular disease risk. However, the role of this environmental factor in atherothrombosis remains undefined. To analyze the impact of gut microbiota on atherothrombosis, we rederived low-density lipoprotein receptor-deficient (Ldlr−/−) mice as germfree (GF) and kept these mice for 16 weeks on an atherogenic high-fat Western diet (HFD) under GF isolator conditions and under conventionally raised specific-pathogen-free conditions (CONV-R). In spite of reduced diversity of the cecal gut microbiome, caused by atherogenic HFD, GF Ldlr−/− mice and CONV-R Ldlr−/− mice exhibited atherosclerotic lesions of comparable sizes in the common carotid artery. In contrast to HFD-fed mice, showing no difference in total cholesterol levels, CONV-R Ldlr−/− mice fed control diet (CD) had significantly reduced total plasma cholesterol, very-low-density lipoprotein (VLDL), and LDL levels compared with GF Ldlr−/− mice. Myeloid cell counts in blood as well as leukocyte adhesion to the vessel wall at the common carotid artery of GF Ldlr−/− mice on HFD were diminished compared to CONV-R Ldlr−/− controls. Plasma cytokine profiling revealed reduced levels of the proinflammatory chemokines CCL7 and CXCL1 in GF Ldlr−/− mice, whereas the T-cell-related interleukin 9 (IL-9) and IL-27 were elevated. In the atherothrombosis model of ultrasound-induced rupture of the common carotid artery plaque, thrombus area was significantly reduced in GF Ldlr−/− mice relative to CONV-R Ldlr−/− mice. Ex vivo, this atherothrombotic phenotype was explained by decreased adhesion-dependent platelet activation and thrombus growth of HFD-fed GF Ldlr−/− mice on type III collagen. IMPORTANCE Our results demonstrate a functional role for the commensal microbiota in atherothrombosis. In a ferric chloride injury model of the carotid artery, GF C57BL/6J mice had increased occlusion times compared to colonized controls. Interestingly, in late atherosclerosis, HFD-fed GF Ldlr−/− mice had reduced plaque rupture-induced thrombus growth in the carotid artery and diminished ex vivo thrombus formation under arterial flow conditions. |
| format |
article |
| author |
Klytaimnistra Kiouptsi Sven Jäckel Giulia Pontarollo Alexandra Grill Marijke J. E. Kuijpers Eivor Wilms Christian Weber Felix Sommer Magdolna Nagy Carlos Neideck Yvonne Jansen Stefanie Ascher Henning Formes Cornelia Karwot Franziska Bayer Bettina Kollar Saravanan Subramaniam Michael Molitor Philip Wenzel Philip Rosenstiel Hristo Todorov Susanne Gerber Ulrich Walter Kerstin Jurk Johan W. M. Heemskerk Emiel P. C. van der Vorst Yvonne Döring Christoph Reinhardt |
| author_facet |
Klytaimnistra Kiouptsi Sven Jäckel Giulia Pontarollo Alexandra Grill Marijke J. E. Kuijpers Eivor Wilms Christian Weber Felix Sommer Magdolna Nagy Carlos Neideck Yvonne Jansen Stefanie Ascher Henning Formes Cornelia Karwot Franziska Bayer Bettina Kollar Saravanan Subramaniam Michael Molitor Philip Wenzel Philip Rosenstiel Hristo Todorov Susanne Gerber Ulrich Walter Kerstin Jurk Johan W. M. Heemskerk Emiel P. C. van der Vorst Yvonne Döring Christoph Reinhardt |
| author_sort |
Klytaimnistra Kiouptsi |
| title |
The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice |
| title_short |
The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice |
| title_full |
The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice |
| title_fullStr |
The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice |
| title_full_unstemmed |
The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice |
| title_sort |
microbiota promotes arterial thrombosis in low-density lipoprotein receptor-deficient mice |
| publisher |
American Society for Microbiology |
| publishDate |
2019 |
| url |
https://doaj.org/article/20c67fc195d04a29b3eecc489e3dc276 |
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