A novel role for miR-133a in centrally mediated activation of the renin-angiotensin system in congestive heart failure

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 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 3´-untranslated region (3´UTR) of AGT and found potential binding site for microRNA-133a(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 Ang II-type1 receptor (AT1) mRNA levels, respectively. Luciferase reporter assay performed on NG108 cells confirmed miR-133a binding to 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 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 microinjectioned Ang II within the PVN of CHF rats. These results reveal a novel and potentially unique role for miR-133a in the regulation of AngII within the PVN of CHF rats, which may potentially contribute to the commonly observed sympathoexcitation in CHF.