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J. Biol. Chem., Vol. 282, Issue 33, 24262-24269, August 17, 2007

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The Human Angiotensin II Type 1 Receptor +1166 A/C Polymorphism Attenuates MicroRNA-155 Binding^*

Mickey M. Martin, Jessica A. Buckenberger, Jinmai Jiang, Geraldine E. Malana, Gerard J. Nuovo^¶, Maqsood Chotani, David S. Feldman^||, Thomas D. Schmittgen, and Terry S. Elton^**1

From the ^**College of Pharmacy, Division of Pharmacology and Division of Pharmaceutics, College of Medicine, the ^¶Department of Pathology and the ^||Department of Medicine, Division of Cardiology, and the Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio 43210

The adverse effects of angiotensin II (Ang II) are primarily mediated through the Ang II type 1 receptor (AT₁R). A silent polymorphism (+1166 A/C) in the human AT₁R gene has been associated with cardiovascular disease, possibly as a result of enhanced AT₁R activity. Because this polymorphism occurs in the 3'-untranslated region of the human AT₁R gene, the biological importance of this mutation has always been questionable. Computer alignment demonstrated that the +1166 A/C polymorphism occurred in a cis-regulatory site, which is recognized by a specific microRNA (miRNA), miR-155. miRNAs are noncoding RNAs that silence gene expression by base-pairing with complementary sequences in the 3'-untranslated region of target RNAs. When the +1166 C-allele is present, base-pairing complementarity is interrupted, and the ability of miR-155 to interact with the cis-regulatory site is decreased. As a result, miR-155 no longer attenuates translation as efficiently as demonstrated by luciferase reporter and Ang II radioreceptor binding assays. In situ hybridization experiments demonstrated that mature miR-155 is abundantly expressed in the same cell types as the AT₁R (e.g. endothelial and vascular smooth muscle). Finally, when human primary vascular smooth muscle cells were transfected with an antisense miR-155 inhibitor, endogenous human AT₁R expression and Ang II-induced ERK1/2 activation were significantly increased. Taken together, our study demonstrates that the AT₁R and miR-155 are co-expressed and that miR-155 translationally represses the expression of AT₁R in vivo. Therefore, our study provides the first feasible biochemical mechanism by which the +1166 A/C polymorphism can lead to increased AT₁R densities and possibly cardiovascular disease.

Received for publication, February 5, 2007 , and in revised form, June 21, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Davis Heart and Lung Research Institute, The Ohio State University, DHLRI 515, 473 West 12th Ave., Columbus, OH 43210. Tel.: 614-292-1400; Fax: 614-247-7799; E-mail: terry.elton{at}osumc.edu.

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