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Emerging roles of let?7d in attenuating pulmonary arterial hypertension via suppression of pulmonary artery endothelial cell autophagy and endothelin synthesis through ATG16L1 downregulation.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a severe disease characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance, resulting in right ventricular failure and death. Compelling evidence has suggested the roles of microRNAs (miRNAs/miRs) in PAH. The present study investigated the possible effects of miR?let?7d on PAH through autophagy?related 16?like 1 (ATG16L1). Initially, the serum levels of let?7d in PAH patients were detected. Rats were then treated with monocrotaline to induce a rat model of PAH, after which the right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) were determined. Next, the putative binding sites between let?7d and ATG16L1 were detected. The expression of let?7d and ATG16L1 in PAH rat models and cells was upregulated or downregulated to assess the effects of these molecules on autophagy in pulmonary artery vascular endothelial cells (PAECs) and on endothelin synthesis. In addition, the levels of p62, LC3?I, LC3?II, LC3B and endothelin?1 (ET?1) were assessed. The results obtained revealed that let?7d was downregulated in the serum of PAH patients and rats with PAH. Importantly, ATG16L1 was found to be a target gene of let?7d and let?7d could suppress the expression of ATG16L1. Overexpression of let?7d was found to reduce RVSP and RVHI values. Additionally, upregulation of let?7d or depletion of ATG16L1 led to suppression of PAEC autophagy and endothelin synthesis, corresponding to decreased ratios of LC3?II to LC3?I and reduced levels of LC3B but elevated levels of p62 in PAECs and ET?1 in plasma and lung tissues. In summary, let?7d upregulation alleviates PAH by inhibiting autophagy in PAECs and suppressing endothelin synthesis through negative regulation of ATG16L1.

SUBMITTER: Ou M

PROVIDER: S-EPMC7255485 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Emerging roles of let‑7d in attenuating pulmonary arterial hypertension via suppression of pulmonary artery endothelial cell autophagy and endothelin synthesis through ATG16L1 downregulation.

Ou Minghui M Li Xia X Cui Shichao S Zhao Shibo S Tu Jie J

International journal of molecular medicine 20200407 1

Pulmonary arterial hypertension (PAH) is a severe disease characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance, resulting in right ventricular failure and death. Compelling evidence has suggested the roles of microRNAs (miRNAs/miRs) in PAH. The present study investigated the possible effects of miR‑let‑7d on PAH through autophagy‑related 16‑like 1 (ATG16L1). Initially, the serum levels of let‑7d in PAH patients were detected. Rats were then treated with monocro ...[more]

PMID: 32319531

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Project description:Contraction of human pulmonary artery smooth muscle cells (HPASMC) isolated from pulmonary arterial hypertensive (PAH) and normal (non-PAH) subject lungs was determined and measured with real-time electrical impedance. Treatment of HPASMC with vasoactive peptides, endothelin-1 (ET-1) and bradykinin (BK) but not angiotensin II, induced a temporal decrease in the electrical impedance profile mirroring constrictive morphological change of the cells which typically was more robust in PAH as opposed to non-PAH cells. Inhibition with LIMKi3 and a cofilin targeted motif mimicking cell permeable peptide (MMCPP) had no effect on ET-1 induced HPASMC contraction indicating a negligible role for these actin regulatory proteins. On the other hand, a MMCPP blocking the activity of caldesmon reduced ET-1 promoted contraction pointing to a regulatory role of this protein and its activation pathway in HPASMC contraction. Inhibition of this MEK/ERK/p90RSK pathway, which is an upstream regulator of caldesmon phosphorylation, reduced ET-1 induced cell contraction. While the regulation of ET-1 induced cell contraction was found to be similar in PAH and non-PAH cells, a key difference was the response to pharmacological inhibitors and to siRNA knockdown of Rho kinases (ROCK1/ROCK2). The PAH cells required much higher concentrations of inhibitors to abrogate ET-1 induced contractions and their contraction was not affected by siRNA against either ROCK1 or ROCK2. Lastly, blocking of L-type and T-type Ca2+ channels had no effect on ET-1 or BK induced contraction. However, inhibiting the activity of the sarcoplasmic reticulum Ca2+ ATPase blunted ET-1 and BK induced HPASMC contraction in both PAH and non-PAH derived HPASMC. In summary, our findings here together with previous communications illustrate similarities and differences in the regulation PAH and non-PAH smooth muscle cell contraction relating to calcium translocation, RhoA/ROCK signaling and the activity of caldesmon. These findings may provide useful tools in achieving the regulation of the vascular hypercontractility taking place in PAH.

Project description:BackgroundPulmonary arterial hypertension is a devastating disease, which leads to right heart failure and premature death. Recent evidence suggests that endothelin receptor antagonists may be promising drugs in the treatment of pulmonary arterial hypertension.ObjectivesTo evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension.Search methodsWe searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of January 2012.Selection criteriaWe included randomised trials (RCTs) and quasi-randomised trials involving patients with pulmonary arterial hypertension.Data collection and analysisFive review authors independently selected studies, assessed study quality and extracted data.Main resultsWe included 12 randomised controlled trials involving 1471 patients. All the trials were of relatively short duration (12 weeks to six months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.71 metres (95% confidence interval (CI) 24.90 to 42.52 metres) further than those treated with placebo in a six-minute walk test. Endothelin receptor antagonists improved more patients' World Health Organization/New York Heart Association (WHO/NYHA) functional class status than placebo (odds ratio (OR) 1.60; 95% CI 1.20 to 2.14), and reduced the odds of functional class deterioration compared with placebo (OR 0.26; 95% CI 0.16 to 0.42). There was a reduction in mortality that did not reach statistical significance on endothelin receptor antagonists (OR 0.57; 95% CI 0.26 to 1.24), and limited data suggest that endothelin receptor antagonists improve the Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population. However, several cases of irreversible liver failure caused by sitaxsentan have been reported that led to license holder for sitaxsentan to withdraw the product from all markets worldwide.Authors' conclusionsEndothelin receptor antagonists can increase exercise capacity, improve WHO/NYHA functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III. However, there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension. Efficacy data are strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in patients treated with endothelin receptor antagonists.

Project description:IntroductionInflammation is a major pathological feature of pulmonary arterial hypertension (PAH), particularly in the context of inflammatory conditions such as systemic sclerosis (SSc). The endothelin system and anti-endothelin A receptor (ETA) autoantibodies have been implicated in the pathogenesis of PAH, and endothelin receptor antagonists are routinely used treatments for PAH. However, immunological functions of the endothelin B receptor (ETB) remain obscure.MethodsSerum levels of anti-ETB receptor autoantibodies were quantified in healthy donors and SSc patients with or without PAH. Age-dependent effects of overexpression of prepro-endothelin-1 or ETB deficiency on pulmonary inflammation and the cardiovascular system were studied in mice. Rescued ETB-deficient mice (ETB -/-) were used to prevent congenital Hirschsprung disease. The effects of pulmonary T-helper type 2 (Th2) inflammation on PAH-associated pathologies were analyzed in ETB -/- mice. Pulmonary vascular hemodynamics were investigated in isolated perfused mouse lungs. Hearts were assessed for right ventricular hypertrophy. Pulmonary inflammation and collagen deposition were assessed via lung microscopy and bronchoalveolar lavage fluid analyses.ResultsAnti-ETB autoantibody levels were elevated in patients with PAH secondary to SSc. Both overexpression of prepro-endothelin-1 and rescued ETB deficiency led to pulmonary hypertension, pulmonary vascular hyperresponsiveness, and right ventricular hypertrophy with accompanying lymphocytic alveolitis. Marked perivascular lymphocytic infiltrates were exclusively found in ETB -/- mice. Following induction of pulmonary Th2 inflammation, PAH-associated pathologies and perivascular collagen deposition were aggravated in ETB -/- mice.ConclusionThis study provides evidence for an anti-inflammatory role of ETB. ETB seems to have protective effects on Th2-evoked pathologies of the cardiovascular system. Anti-ETB autoantibodies may modulate ETB-mediated immune homeostasis.

Dataset Information

Emerging roles of let?7d in attenuating pulmonary arterial hypertension via suppression of pulmonary artery endothelial cell autophagy and endothelin synthesis through ATG16L1 downregulation.

Publications

Emerging roles of let‑7d in attenuating pulmonary arterial hypertension via suppression of pulmonary artery endothelial cell autophagy and endothelin synthesis through ATG16L1 downregulation.

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