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Downregulated microRNA?133a induces HUVECs injury: Potential role of the (pro) renin receptor in angiotensin II?dependent hypertension.

ABSTRACT: The renin?angiotensin system (RAS) serves an essential role in hypertension. MicroRNAs (miRs) have been reported to be important regulators in angiotensin (Ang) II?dependent hypertension. We aimed to explore the roles of Ang II and miR?133a in the mechanism underlying hypertension. Human umbilical vein endothelial cells (HUVECs) were identified by immunofluorescence staining. Cell viability and miR?133a expression under the inhibition of Ang II of various concentrations were determined by an MTT assay and reverse transcription?quantitative polymerase chain reaction (RT?qPCR), respectively. The effects of HUVECs transfected with miR?133a mimic or inhibitor on Ang II?induced apoptosis were measured using flow cytometry. The potential targeting of miR?133a to the 3' untranslated region of (pro) renin receptor (PRR) was assessed using TargetScan and a dual?luciferase assay. The effects of PRR interference using small interfering (si)RNA on PRR expression and the rate of apoptosis were determined by RT?qPCR, western blotting and flow cytometry, respectively. Ang II at a concentration of 10?5 M significantly inhibited the cell viability (P<0.05) and miR?133a expression (P<0.01); Downregulation of miR?133a suppressed cell viability. HUVECs transfected with miR?133a mimic reduced the rate of Ang II?induced apoptosis from 21.99 to 12.38%, but miR?133a inhibitor promoted Ang II?induced apoptosis (apoptosis rate, 28.9%). PRR was predicted to be a target gene of miR?133a. Transfection with siPRR decreased the apoptotic rate in Ang II + negative control and Ang II + miR?133a inhibitor group to 11.39 and 12.94%, respectively. Our findings also suggested that Ang II promoted PRR expression to enhance the apoptotic rate of HUVECs via the suppression of miR?133a. Furthermore, siPRR efficiently decreased the Ang II?induced apoptosis.

SUBMITTER: Liu B

PROVIDER: S-EPMC6691251 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Downregulated microRNA‑133a induces HUVECs injury: Potential role of the (pro) renin receptor in angiotensin II‑dependent hypertension.

Liu Bing B Lan Ming M Wei Huali H Zhang Dapeng D Liu Junmeng J Teng Jiwei J

Molecular medicine reports 20190723 3

The renin‑angiotensin system (RAS) serves an essential role in hypertension. MicroRNAs (miRs) have been reported to be important regulators in angiotensin (Ang) II‑dependent hypertension. We aimed to explore the roles of Ang II and miR‑133a in the mechanism underlying hypertension. Human umbilical vein endothelial cells (HUVECs) were identified by immunofluorescence staining. Cell viability and miR‑133a expression under the inhibition of Ang II of various concentrations were determined by an MTT ...[more]

PMID: 31524252

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Project description:RationalePatients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are up-regulated, but this may have long-term negative effects on the progression of iPAH.ObjectivesAssess systemic and pulmonary RAAS activity in patients with iPAH and determine the efficacy of chronic RAAS inhibition in experimental PAH.MethodsWe collected 79 blood samples from 58 patients with iPAH in the VU University Medical Center Amsterdam (between 2004 and 2010) to determine systemic RAAS activity.Measurements and main resultsWe observed increased levels of renin, angiotensin (Ang)I, and AngII, which were associated with disease progression (P < 0.05) and mortality (P < 0.05). To determine pulmonary RAAS activity, lung specimens were obtained from patients with iPAH (during lung transplantation, n = 13) and control subjects (during lobectomy or pneumonectomy for cancer, n = 14). Local RAAS activity in pulmonary arteries of patients with iPAH was increased, demonstrated by elevated angiotensin-converting enzyme activity in pulmonary endothelial cells and increased AngII type 1 (AT(1)) receptor expression and signaling. In addition, local RAAS up-regulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT(1) receptor signaling in patients with iPAH compared with control subjects. Finally, to determine the therapeutic potential of RAAS activity, we assessed the chronic effects of an AT(1) receptor antagonist (losartan) in the monocrotaline PAH rat model (60 mg/kg). Losartan delayed disease progression, decreased right ventricular afterload and pulmonary vascular remodeling, and restored right ventricular-arterial coupling in rats with PAH.ConclusionsSystemic and pulmonary RAAS activities are increased in patients with iPAH and are associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH.

Project description:Improper regulation of signaling in vascular smooth muscle cells (VSMCs) by angiotensin II (AngII) can lead to hypertension, vascular hypertrophy and atherosclerosis. The extent to which the homeostatic levels of the components of signaling networks are regulated through microRNAs (miRNA) modulated by AngII type 1 receptor (AT1R) in VSMCs is not fully understood. Whether AT1R blockers used to treat vascular disorders modulate expression of miRNAs is also not known. To report differential miRNA expression following AT1R activation by AngII, we performed microarray analysis in 23 biological and technical replicates derived from humans, rats and mice. Profiling data revealed a robust regulation of miRNA expression by AngII through AT1R, but not the AngII type 2 receptor (AT2R). The AT1R-specific blockers, losartan and candesartan antagonized >90% of AT1R-regulated miRNAs and AngII-activated AT2R did not modulate their expression. We discovered VSMC-specific modulation of 22 miRNAs by AngII, and validated AT1R-mediated regulation of 17 of those miRNAs by real-time polymerase chain reaction analysis. We selected miR-483-3p as a novel representative candidate for further study because mRNAs of multiple components of the renin-angiotensin system (RAS) were predicted to contain the target sequence for this miRNA. MiR-483-3p inhibited the expression of luciferase reporters bearing 3'-UTRs of four different RAS genes and the inhibition was reversed by antagomir-483-3p. The AT1R-regulated expression levels of angiotensinogen and angiotensin converting enzyme 1 (ACE-1) proteins in VSMCs are modulated specifically by miR-483-3p. Our study demonstrates that the AT1R-regulated miRNA expression fingerprint is conserved in VSMCs of humans and rodents. Furthermore, we identify the AT1R-regulated miR-483-3p as a potential negative regulator of steady-state levels of RAS components in VSMCs. Thus, miRNA-regulation by AngII to affect cellular signaling is a novel aspect of RAS biology, which may lead to discovery of potential candidate prognostic markers and therapeutic targets.

Dataset Information

Downregulated microRNA?133a induces HUVECs injury: Potential role of the (pro) renin receptor in angiotensin II?dependent hypertension.

Publications

Downregulated microRNA‑133a induces HUVECs injury: Potential role of the (pro) renin receptor in angiotensin II‑dependent hypertension.

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