The human angiotensin II type 1 receptor +1166 A/C polymorphism attenuates microRNA-155 binding
Authors: David S Feldman
Gerard J Nuovo
Jinmai Jiang
Maqsood Chotani
Jessica A Buckenberger
Geraldine E Malana
Terry S Elton
Mickey M Martin
Thomas D Schmittgen
Journal: Journal of Biological Chemistry (2007)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Angiotensin II; AT1R; polymorphism; miRNA; miR-155
Affiliations: Davis Heart and Lung Institute, The Ohio State University, Ohio 43210, USA.

Abstract:  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 AT(1)R 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. 

Retracted: Yes

PubPeer comments:
 https: www.federalregister.gov documents 2012 12 26 2012-30866 findings-of-research-misconduct SUMMARY: Notice is hereby given that the Office of Research Integrity (ORI) has taken final action in the following case: Terry S. Elton, Ph.D., The Ohio State University: Based on the reports of two investigations conducted by The Ohio State University (OSU) and additional analysis conducted by ORI in its oversight review, ORI found that Dr. Terry S. Elton, Professor, College of Pharmacy and Davis Heart and Lung Research Institute, OSU, engaged in research misconduct in research supported by National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), grants R01 HL048848, R01 HL084498, and P01 HL70294, National Institute of Child Health and Human Development (NICHD), NIH, grant R21 HD058997, National Institute on Aging (NIA), NIH, grant R01 AG021912, National Institute of Allergy and Infectious Diseases (NIAID), NIH, grant R01 AI39963, and National Eye Institute (NEI), NIH, grant R01 ES012241. ORI found that the Respondent engaged in research misconduct by falsifying and or fabricating data that were included in 1 R21 HD058997-01, 1 R21 HD058997-01A1, 1 R21 HD058997-01A2, 1 RC1 HL100298-01, and in: 1. Kuhn, D.E., Nuovo, G.J., Terry, A.V. Jr., Martin, M.M., Malana, G.E., Sansom, SE., Pleister, A.P., Beck, W.D., Head, E., Feldman, D.S., Elton, T.S. u201cChromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains.u201d J Biol Chem 285(2):1529-43, 2010 Jan 8. 2. Kuhn, D.E., Nuovo, G.J., Martin, M.M., Malana, G.E., Pleister, A.P., Jiang, J., Schmittgen, T.D., Terry, A.V. Jr., Gardiner, K., Head, E., Feldman, D.S., Elton, T.S. u201cHuman chromosome 21-derived miRNAs are overexpressed in Down syndrome brains and hearts.u201d Biochem Biophys Res Commun 370(3):473-7, 2008 Jun 6. 3. Martin, M.M., Buckenberger, J.A., Jiang, J., Malana, G.E., Knoell, D.L., Feldman, D.S., Elton, T.S. u201cTGFu00df1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways.u201d Am. J. Physiol. Lung Cell. Mol. Physiol. 293(3):L790-9, 2007 Sept. (Retracted: Am. J. Physiol. Lung Cell. Mol. Physiol. 302(7):L719, 2012 Apr.) 4. Martin, M.M., Buckenberger, J.A., Jiang, J., Malana, G.E., Nuovo, G.J., Chotani, M., Feldman, D.S., Schmittgen, T.D., Elton, T.S. u201cThe human angiotensin II type 1 receptor +1166 A C polymorphism attenuates microRNA-155 binding.u201d J Biol Chem 282(33):24262-9, 2007, Aug 17. 5. Martin, M.M., Buckenberger, J.A., Knoell, D.L., Strauch, A.R., Elton, T.S. u201cTGF-beta(1) regulation of human AT1 receptor mRNA splice variants harboring exon 2.u201d Mol Cell Endocrinol 249(1-2):21-31, 2006 Apr 25. 6. Duffy, A.A., Martin, M.M., Elton, T.S. u201cTranscriptional regulation of the AT1 receptor gene in immortalized human trophoblast cells.u201d Biochim. Biophys. Acta. 1680(3):158-70, 2004 Nov 5. As a result of its investigation, OSU has recommended that all of the above publications be retracted. Specifically, ORI finds that Respondent: Falsified and or fabricated Western blots in an NIH grant application in three submissions of the same grant application: u25b8 Figures 4, 7, 11C: 1 R21 HD058997-01 u25b8 Figures 7B, 7E, 8B: 1 R21 HD058997-01A1 u25b8 Figures 3C, 3F, 6C: 1 R21 HD058997-01A2 and false Western blots were also included in Figure 6 in grant application 1 RC1 HL100298-01. Falsified and or fabricated Western blots in eighteen (18) figures and in six (6) published papers. Specifically false and or fabricated images were included in: u25b8 Figures 2C, 2D, 2F, 3C, 3E, 4G, 5C, 5F: J Biol Chem 285(2):1529-43, 2010 Jan 8 u25b8 Figures 3B, 3C, 3F, 3H, 3I, 3J: Biochem Biophys Res Commun 370(3):473-7, 2008 Jun 6 u25b8 Figures 2, 3, 4B, 5B, 6, 7B, 8A, 9B: Am. J. Physiol. Lung Cell. Mol. Physiol. 293(3):L790-9, 2007 Sept u25b8 Figure 6: J Biol Chem 282(33):24262-9, 2007 Aug 17 u25b8 Figure 6: Mol Cell Endocrinol 249(1-2):21-31, 2006 Apr 25 u25b8 Figures 5, 6B, 7B, 9B: Biochim. Biophys. Acta 1680(3):158-70, 2004 Nov 5. Dr. Elton has entered into a Voluntary Exclusion Agreement and has voluntarily agreed: (1) To exclude himself from any contracting or subcontracting with any agency of the United States Government and from eligibility or involvement in nonprocurement programs of the United States Government referred to as u201ccovered transactionsu201d pursuant to HHS Implementation (2 CFR part 376 et seq.) of OMB Guidelines to Agencies on Govermentwide Debarment and Suspension, 2 CFR part 180 (collectively the u201cDebarment Regulationsu201d) for a period of three (3) years, beginning on November 26, 2012; (2) To exclude himself voluntarily from serving in any advisory capacity to PHS including, but not limited to, service on any PHS advisory committee, board, and or peer review committee, or as a consultant for a period of three (3) years, beginning on November 26, 2012; and (3) To request that the following publications be retracted: J Biol Chem 285(2):1529-43, 2010 Jan 8 Biochem Biophys Res Commun 370(3):473-7, 2008 Jun 6 J Biol Chem 282(33):24262-9, 2007, Aug 17 Mol Cell Endocrinol 249(1-2):21-31, 2006 Apr 25 Biochim. Biophys. Acta. 1680(3):158-70, 2004 Nov 5. (omitted) *** For convenience, here is Figure 6 ![file] *** And a false color illustration ![file] ,