title: A novel role for miR-133a in centrally mediated activation of the renin-angiotensin system in congestive heart failure.
abstract: An activated renin-angiotensin system (RAS) within the central nervous system has been implicated in sympathoexcitation during various disease conditions including congestive heart failure (CHF). In particular, activation of the RAS in the paraventricular nucleus (PVN) of the hypothalamus has been recognized to augment sympathoexcitation in CHF. We observed a 2.6-fold increase in angiotensinogen (AGT) in the PVN of CHF. To elucidate the molecular mechanism for increased expression of AGT, we performed in silico analysis of the 3'-untranslated region (3'-UTR) of AGT and found a potential binding site for microRNA (miR)-133a. We hypothesized that decreased miR-133a might contribute to increased AGT in the PVN of CHF rats. Overexpression of miR-133a in NG108 cells resulted in 1.4- and 1.5-fold decreases in AGT and angiotensin type II (ANG II) type 1 receptor (AT1R) mRNA levels, respectively. A luciferase reporter assay performed on NG108 cells confirmed miR-133a binding to the 3'-UTR of AGT. Consistent with these in vitro data, we observed a 1.9-fold decrease in miR-133a expression with a concomitant increase in AGT and AT1R expression within the PVN of CHF rats. Furthermore, restoring the levels of miR-133a within the PVN of CHF rats with viral transduction resulted in a significant reduction of AGT (1.4-fold) and AT1R (1.5-fold) levels with a concomitant decrease in basal renal sympathetic nerve activity (RSNA). Restoration of miR-133a also abrogated the enhanced RSNA responses to microinjected ANG II within the PVN of CHF rats. These results reveal a novel and potentially unique role for miR-133a in the regulation of ANG II within the PVN of CHF rats, which may potentially contribute to the commonly observed sympathoexcitation in CHF.NEW & NOTEWORTHYAngiotensinogen (AGT) expression is upregulated in the paraventricular nucleus of the hypothalamus through posttranscriptional mechanism interceded by microRNA-133a in heart failure. Understanding the mechanism of increased expression of AGT in pathological conditions leading to increased sympathoexcitation may provide the basis for the possible development of new therapeutic agents with enhanced specificity.
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; and nsharma@unmc.edu.
authors.forename: Neeru M
authors.initials: NM
authors.lastname: Sharma
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; and.
authors.forename: Shyam S
authors.identifier: http://orcid.org/0000-0001-6422-2540
authors.initials: SS
authors.lastname: Nandi
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; and.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; and.|Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Paras K
authors.initials: PK
authors.lastname: Mishra
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; and.
authors.forename: Kaushik P
authors.initials: KP
authors.lastname: Patel
mesh_terms: D020413:3' Untranslated Regions; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology; D007668:Kidney / Q000294:innervation; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D010286:Paraventricular Hypothalamic Nucleus / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D047228:Angiotensin II Type 1 Receptor Blockers; C549446:MIRN133 microRNA, rat; D035683:MicroRNAs; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D019808:Losartan
keywords: angiotensin II; congestive heart failure; miR-133a; microRNA; paraventricular nucleus; sympathoexcitation