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Maliheh Nazari-Jahantigh,
Yuanyuan Wei, Heidi Noels,
Shamima Akhtar,
Zhe Zhou,
Rory R Koenen,
Kathrin Heyll,
Felix Gremse,
Fabian Kiessling,
Jochen Grommes,
Christian Weber,
Andreas Schober
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ABSTRACT: Macrophages in atherosclerotic plaques drive inflammatory responses, degrade lipoproteins, and phagocytose dead cells. MicroRNAs (miRs) control the differentiation and activity of macrophages by regulating the signaling of key transcription factors. However, the functional role of macrophage-related miRs in the immune response during atherogenesis is unknown. Here, we report that miR-155 is specifically expressed in atherosclerotic plaques and proinflammatory macrophages, where it was induced by treatment with mildly oxidized LDL (moxLDL) and IFN-γ. Leukocyte-specific Mir155 deficiency reduced plaque size and number of lesional macrophages after partial carotid ligation in atherosclerotic (Apoe-/-) mice. In macrophages stimulated with moxLDL/IFN-γ in vitro, and in lesional macrophages, loss of Mir155 reduced the expression of the chemokine CCL2, which promotes the recruitment of monocytes to atherosclerotic plaques. Additionally, we found that miR-155 directly repressed expression of BCL6, a transcription factor that attenuates proinflammatory NF-κB signaling. Silencing of Bcl6 in mice harboring Mir155-/- macrophages enhanced plaque formation and CCL2 expression. Taken together, these data demonstrated that miR-155 plays a key role in atherogenic programming of macrophages to sustain and enhance vascular inflammation.
The Journal of clinical investigation 10/2012; · 15.39 Impact Factor
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Cardiovascular Drugs and Therapy 04/2012; 24(1):1-3. · 3.13 Impact Factor
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ABSTRACT: The greatest challenge of scientific research is to understand the causes and consequences of disease. In recent years, great efforts have been devoted to unraveling the basic mechanisms of atherosclerosis (the underlying pathology of cardiovascular disease), which remains a major cause of morbidity and mortality worldwide. Because of the complex and multifactorial pathophysiology of cardiovascular disease, different research techniques have increasingly been combined to unravel genetic aspects, molecular pathways, and cellular functions involved in atherogenesis, vascular inflammation, and dyslipidemia to gain a multifaceted picture addressing this complexity. Thanks to the rapid evolution of high-throughput technologies, we are now able to generate large-scale data on the DNA, RNA, and protein levels. With the help of sophisticated computational tools, these data sets are integrated to enhance information extraction and are being increasingly used in a systems biology approach to model biological processes as interconnected and regulated networks. This review exemplifies the use of high-throughput technologies-such as genomics, transcriptomics, proteomics, and epigenomics-and systems biology to explore pathomechanisms of vascular inflammation and atherosclerosis.
Arteriosclerosis Thrombosis and Vascular Biology 02/2012; 32(2):182-95. · 6.37 Impact Factor
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Current opinion in lipidology 04/2011; 22(2):144-5. · 6.13 Impact Factor
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ABSTRACT: Coronary artery disease (CAD) arising from atherosclerosis is a leading cause of death and morbidity worldwide. The underlying pathogenesis involves an imbalanced lipid metabolism and a maladaptive immune response entailing a chronic inflammation of the arterial wall. The disturbed equilibrium of lipid accumulation, immune responses and their clearance is shaped by leukocyte trafficking and homeostasis governed by chemokines and their receptors. New pro- and anti-inflammatory pathways linking lipid and inflammation biology have been discovered, and genetic profiling studies have unveiled variations involved in human CAD. The growing understanding of the inflammatory processes and mediators has uncovered an intriguing diversity of targetable mechanisms that can be exploited to complement lipid-lowering therapies. Here we aim to systematically survey recently identified molecular mechanisms, translational developments and clinical strategies for targeting lipid-related inflammation in atherosclerosis and CAD.
Nature medicine 01/2011; 17(11):1410-22. · 27.14 Impact Factor
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Cardiovascular Drugs and Therapy 02/2010; 24(1):1-3. · 3.13 Impact Factor
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ABSTRACT: In the recent years, atherogenesis has increasingly been linked to inflammatory processes in the injured vessel wall. Recruitment and arrest of monocytes, T cells, and neutrophils via the concerted actions of multiple chemokines and their chemokine receptors have been the subject of intense research and are being appreciated as key events underlying atherosclerotic lesion formation and progression. The evolutionary conserved cytokine macrophage migration inhibitory factor (MIF) exhibits prominent proinflammatory and proatherogenic functions, and the latest findings on its chemotactic and chemokine-like properties imply MIF as a crucial drug target for the treatment of inflammatory diseases. In this review, the role of MIF in atherosclerosis and injury-induced neointima formation is discussed. We place an emphasis on its proinflammatory and chemokine-like functions in the context of underlying extra- and intracellular signaling mechanisms. These findings clearly distinguish MIF from other cytokines in atherosclerosis and justify the intensive search for inhibitors targeting MIF in the treatment of inflammatory diseases, including advanced atherosclerosis.
Trends in cardiovascular medicine 05/2009; 19(3):76-86. · 4.37 Impact Factor
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Alma Zernecke,
Kiril Bidzhekov, Heidi Noels,
Erdenechimeg Shagdarsuren,
Lin Gan,
Bernd Denecke,
Mihail Hristov,
Thomas Köppel,
Maliheh Nazari Jahantigh,
Esther Lutgens,
Shusheng Wang,
Eric N Olson,
Andreas Schober,
Christian Weber
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ABSTRACT: Apoptosis is a pivotal process in embryogenesis and postnatal cell homeostasis and involves the shedding of membranous microvesicles termed apoptotic bodies. In response to tissue damage, the CXC chemokine CXCL12 and its receptor CXCR4 counteract apoptosis and recruit progenitor cells. Here, we show that endothelial cell-derived apoptotic bodies are generated during atherosclerosis and convey paracrine alarm signals to recipient vascular cells that trigger the production of CXCL12. CXCL12 production was mediated by microRNA-126 (miR-126), which was enriched in apoptotic bodies and repressed the function of regulator of G protein (heterotrimeric guanosine triphosphate-binding protein) signaling 16, an inhibitor of G protein-coupled receptor (GPCR) signaling. This enabled CXCR4, a GPCR, to trigger an autoregulatory feedback loop that increased the production of CXCL12. Administration of apoptotic bodies or miR-126 limited atherosclerosis, promoted the incorporation of Sca-1+ progenitor cells, and conferred features of plaque stability on different mouse models of atherosclerosis. This study highlights functions of microRNAs in health and disease that may extend to the recruitment of progenitor cells during other forms of tissue repair or homeostasis.
Science Signaling 01/2009; 2(100):ra81. · 7.50 Impact Factor
