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Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development.
Arterioscler Thromb Vasc Biol. 2013 Jul; 33(7):1529-37.AT

Abstract

OBJECTIVE

Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development.

APPROACH AND RESULTS

Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low-density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis-prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% (P<0.05). In addition, Angptl4 overexpression decreased macrophage content (-41%; P<0.05) and numbers of monocytes adhering to the endothelium wall (-37%; P<0.01). Finally, plasma Angptl4 was independently and negatively associated with carotid artery sclerosis measured by 3-T MRI in subjects with metabolic syndrome and low-grade systemic inflammation.

CONCLUSIONS

Angptl4 suppresses foam cell formation to reduce atherosclerosis development. Stimulation of Angptl4 in macrophages by oxidized low-density lipoprotein may protect against lipid overload.

Authors+Show Affiliations

Nutrition, Metabolism, and Genomics Group, Wageningen University, Wageningen, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23640487

Citation

Georgiadi, Anastasia, et al. "Overexpression of Angiopoietin-like Protein 4 Protects Against Atherosclerosis Development." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 7, 2013, pp. 1529-37.
Georgiadi A, Wang Y, Stienstra R, et al. Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development. Arterioscler Thromb Vasc Biol. 2013;33(7):1529-37.
Georgiadi, A., Wang, Y., Stienstra, R., Tjeerdema, N., Janssen, A., Stalenhoef, A., van der Vliet, J. A., de Roos, A., Tamsma, J. T., Smit, J. W., Tan, N. S., Müller, M., Rensen, P. C., & Kersten, S. (2013). Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development. Arteriosclerosis, Thrombosis, and Vascular Biology, 33(7), 1529-37. https://doi.org/10.1161/ATVBAHA.113.301698
Georgiadi A, et al. Overexpression of Angiopoietin-like Protein 4 Protects Against Atherosclerosis Development. Arterioscler Thromb Vasc Biol. 2013;33(7):1529-37. PubMed PMID: 23640487.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development. AU - Georgiadi,Anastasia, AU - Wang,Yanan, AU - Stienstra,Rinke, AU - Tjeerdema,Nathanja, AU - Janssen,Aafke, AU - Stalenhoef,Anton, AU - van der Vliet,J Adam, AU - de Roos,Albert, AU - Tamsma,Jouke T, AU - Smit,Johannes W A, AU - Tan,Nguan Soon, AU - Müller,Michael, AU - Rensen,Patrick C N, AU - Kersten,Sander, Y1 - 2013/05/02/ PY - 2013/5/4/entrez PY - 2013/5/4/pubmed PY - 2013/8/28/medline KW - atherosclerosis KW - inflammation KW - lipoprotein lipase KW - lipoproteins KW - macrophages SP - 1529 EP - 37 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler Thromb Vasc Biol VL - 33 IS - 7 N2 - OBJECTIVE: Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development. APPROACH AND RESULTS: Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low-density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis-prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% (P<0.05). In addition, Angptl4 overexpression decreased macrophage content (-41%; P<0.05) and numbers of monocytes adhering to the endothelium wall (-37%; P<0.01). Finally, plasma Angptl4 was independently and negatively associated with carotid artery sclerosis measured by 3-T MRI in subjects with metabolic syndrome and low-grade systemic inflammation. CONCLUSIONS: Angptl4 suppresses foam cell formation to reduce atherosclerosis development. Stimulation of Angptl4 in macrophages by oxidized low-density lipoprotein may protect against lipid overload. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/23640487/Overexpression_of_angiopoietin_like_protein_4_protects_against_atherosclerosis_development_ L2 - https://www.ahajournals.org/doi/10.1161/ATVBAHA.113.301698?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -