mRNA-Binding Protein ZFP36 Is Expressed in Atherosclerotic Lesions and Reduces Inflammation in Aortic Endothelial Cells

• Authors: Huanchun Zhang, Emory University; William Taylor, Emory University; Giji Joseph, Emory University; Valentina Caracciolo, Thomas Jefferson University; Donna M. Gonzales, Thomas Jefferson University; Neil Sidell, Emory University; Emre Seli, Yale University; Perry J. Blackshear, National Institute of Environmental Health Sciences; Caleb B. Kallen, Thomas Jefferson University
• Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology
• Volume: Volume 33, Number 6
• Publisher: American Heart Association | 2013-06-01, Pages 1212-+
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1161/ATVBAHA.113.301496
• Subjects: Health Sciences, Medicine and Surgery; Health Sciences, Obstetrics and Gynecology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Hematology; Peripheral Vascular Disease; Cardiovascular System & Cardiology; atherosclerosis; AU-rich element; cytokines; endothelial cell; inflammation; zinc finger protein-36; FACTOR-KAPPA-B; CIRCULATING ENDOTOXIN; INSULIN-RESISTANCE; TNF-ALPHA; IN-VITRO; TRISTETRAPROLIN; MICE; GENE; MACROPHAGES; DEFICIENCY

Abstract

Objective-We studied the expression and function of an mRNA-binding protein, zinc finger protein-36 (ZFP36), in vascular endothelial cells in vivo and in vitro. We tested the hypotheses that ZFP36 regulates inflammation in vascular endothelial cells and that it functions through direct binding to target cytokine mRNAs. We also tested whether ZFP36 inhibits nuclear factor-kB-mediated transcriptional responses in vascular endothelial cells. Approach and Results-ZFP36 was minimally expressed in healthy aorta but was expressed in endothelial cells overlying atherosclerotic lesions in mice and humans. The protein was also expressed in macrophage foam cells of atherosclerosis. ZFP36 was expressed in human aortic endothelial cells in response to bacterial lipopolysaccharide, glucocorticoid, and forskolin, but not oxidized low-density lipoproteins or angiotensin II. Functional studies demonstrated that ZFP36 reduces the expression of inflammatory cytokines in target cells by 2 distinct mechanisms: ZFP36 inhibits nuclear factor-kB transcriptional activation and also binds to cytokine mRNAs, leading to reduced transcript stability. Conclusions-ZFP36 is expressed in vascular endothelial cells and macrophage foam cells where it inhibits the expression of proinflammatory mRNA transcripts. The anti-inflammatory effects of ZFP36 in endothelial cells occur via both transcriptional and posttranscriptional mechanisms. Our data suggest that enhancing vascular ZFP36 expression might reduce vascular inflammation.