Network of MicroRNAs Mediate Translational Repression of Bone Morphogenetic Protein Receptor‐2: Involvement in HIV‐Associated Pulmonary Vascular Remodeling

Abstract

BackgroundEarlier, we reported that the simultaneous exposure of pulmonary arterial smooth muscle cells to HIV proteins and cocaine results in the attenuation of antiproliferative bone morphogenetic protein receptor‐2 (BMPR2) protein expression without any decrease in its mRNA levels. Therefore, in this study, we aimed to investigate the micro RNA‐mediated posttranscriptional regulation of BMPR2 expression.Methods and ResultsWe identified a network of BMPR2 targeting micro RNAs including miR‐216a to be upregulated in response to cocaine and Tat‐mediated augmentation of oxidative stress and transforming growth factor‐β signaling in human pulmonary arterial smooth muscle cells. By using a loss or gain of function studies, we observed that these upregulated micro RNAs are involved in the Tat‐ and cocaine‐mediated smooth muscle hyperplasia via regulation of BMPR2 protein expression. These in vitro findings were further corroborated using rat pulmonary arterial smooth muscle cells isolated from HIV transgenic rats exposed to cocaine. More importantly, luciferase reporter and in vitro translation assays demonstrated that direct binding of novel miR‐216a and miR‐301a to 3′UTR of BMPR2 results in the translational repression of BMPR2 without any degradation of its mRNA.ConclusionsWe identified for the first time miR‐216a as a negative modulator of BMPR2 translation and observed it to be involved in HIV protein(s) and cocaine‐mediated enhanced proliferation of pulmonary smooth muscle cells.

Drug abuse and HIV-related pulmonary hypertension

“…Interestingly, this was accompanied by the significant increase in the mRNA expression of BMPRs. These findings highlight the importance of ubiquitination dependent degradation of BMPRs [130] or post-transcriptional regulation of BMPR expression by miRNAs [131]. Significant increase in the levels of miRNAs known to target BMPR-2 expression such as miR-19a, −20a, −21, −130a and miR301 has been observed after combined treatment of HPASMCs with HIV-Tat and cocaine when compared with mono-treatments [131].…”

“…These findings highlight the importance of ubiquitination dependent degradation of BMPRs [130] or post-transcriptional regulation of BMPR expression by miRNAs [131]. Significant increase in the levels of miRNAs known to target BMPR-2 expression such as miR-19a, −20a, −21, −130a and miR301 has been observed after combined treatment of HPASMCs with HIV-Tat and cocaine when compared with mono-treatments [131]. Furthermore, a novel miR-216a, that was significantly up-regulated after HIV-Tat and cocaine treatment, was found to directly bind to the 3’UTR of BMPR-2 and inhibit translation without the degradation of BMPR-2 mRNA [131].…”

Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension

“…Study of HIV-associated PAH reveals that viral protein products Tat, Nef, and gp-120 reduce BMPR2 expression [ 50 ]. This effect was most dramatic in a combined HIV- and cocaine-mediated PAH model, and it implicates miR-126 and 301a as mechanisms of BMPR2 downregulation [ 51 ].…”

La baja expresión de oxido nítrico sintetasa provoca mayor severidad en las lesiones vasculares complejas asociadas al VIH

“…Once released, it rapidly diffuses across cell membranes to reach the cytoplasm of adjacent vascular smooth muscle cells, where it binds to soluble guanylate cyclase and increases intracellular cyclic guanosine monophosphate (cGMP) levels. cGMP, in turn, phosphorylates cGMP-dependent protein kinase, which acts at several sites within the cell membrane and endoplasmic reticulum to lower intracellular calcium levels and reduce cross-linking of myosin light chain and decrease vascular tone 8 .…”