MicroRNA-212-5p, an anti-proliferative miRNA, attenuates hypoxia and sugen/hypoxia-induced pulmonary hypertension in rodents

Chen, Tianji; Sun, Meng; Zhou, Qingwen; Guzman, Alyssa M.; Ramchandran, Ramaswamy; Chen, Jiwang; Fraidenburg, Dustin R.; Ganesh, Balaji; Maienschein‐Cline, Mark; Obrietan, Karl; Raj, J. Usha

doi:10.1016/j.omtn.2022.06.008

Cited by 11 publications

(5 citation statements)

References 42 publications

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“…30 Besides, miR-212-5p attenuates hypoxia and sugen/hypoxia-induced pulmonary hypertension in rodents. 31 Interestingly, miR-212-5p downregulation has been identified in COPD patients and inhibited the CSE-induced increase in the expression of inflammation and COPD related genes in NCI-H292 cells, suggesting that miR-212-5p may serve as a potential therapeutic target for COPD. 32 In the present study, we demonstrated that the expression of miR-212-5p was remarkably decreased in COPD smokers, suggesting that miR-212-5p might play a significant role in the progression of COPD.…”

Section: Discussionmentioning

confidence: 98%

LINC00599 influences smoke-related chronic obstructive pulmonary disease and regulates CSE-induced epithelial cell apoptosis and inflammation by targeting miR-212-5p/BASP1 axis

Dong

2022

Hum Exp Toxicol

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LINC00599 has been reported to be upregulated in response to cigarette smoking. However, the effect and underlying mechanism of LINC00599 in chronic obstructive pulmonary disease (COPD) are still under exploration. In this study, LINC00599 was upregulated in the COPD patients and was of clinical value to distinguish COPD patients. COPD cell models were established using 16HBE cells under cigarette smoke extract (CSE) treatment. LINC00599 levels were elevated in a dose and time-dependent way in response to CSE stimulation. The effect of LINC00599 on CSE-induced 16HBE cells was explored. The results showed that LINC00599 deficiency reversed the CSE-induced inhibition on cell viability and proliferation, and rescued the CSE-induced enhancement on cell 16HBE cell apoptosis and inflammation response. Moreover, LINC00599 bound with miR-212-5p to upregulate the BASP1 (brain abundant membrane attached signal protein 1) expression. MiR-212-5p was expressed at a low level in the tissue samples of COPD patients, and its levels were upregulated in LINC00599 silenced cells. BASP1 was targeted by miR-212-5p and its upregulation was identified in the tissue samples of COPD patients and cell models. BASP1 levels were downregulated after miR-212-5p overexpression or LINC00599 silencing. Moreover, the rescue assays demonstrated that BASP1 overexpression reversed the effect of silenced LINC00599 on 16HBE cells after CSE treatment, which indicated that LINC00599 promoted the COPD development by regulating BASP1 expression. In conclusion, LINC00599 facilitated CSE-induced cell apoptosis and inflammation response, while inhibiting the cell viability and proliferation in COPD progression via modulating miR-212-5p/BASP1 axis.

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Section: Discussionmentioning

confidence: 98%

LINC00599 influences smoke-related chronic obstructive pulmonary disease and regulates CSE-induced epithelial cell apoptosis and inflammation by targeting miR-212-5p/BASP1 axis

Dong

2022

Hum Exp Toxicol

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“…This experience with EVs in a neonatal condition mirrors the beneficial effects demonstrated by EVbased therapy in adult preclinical models of pulmonary arterial hypertension 52,53 . The regenerative effects of EV administration in these studies have been ascribed in part to the release of miRNAs contained in the EV cargo [53][54][55][56] . This is in line with our previous mechanistic studies, where we demonstrated that one potential mechanism of action of AFSC-EVs is through the delivery of miRNAs to the fetal lungs 20,21 .…”

Section: Discussionmentioning

confidence: 99%

Fetal lung vascular development is disrupted by mechanical compression and rescued by administration of amniotic fluid stem cell extracellular vesicles via regulation of the Hippo signaling pathway

Figueira,

Khalaj,

Antounians

et al. 2023

Preprint

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Postnatal pulmonary hypertension is the biggest treatment challenge and major determinant for poor outcome in infants with congenital diaphragmatic hernia (CDH). CDH lungs are hypoplastic and exhibit vascular remodeling, whose pathogenesis remains poorly understood. Using a novel micro-static compression system, herein we found that mechanical compression induces vascular remodeling and downregulation of key angiogenic markers in rat and human fetal lung models, with similar features observed in CDH fetal lung autopsy samples. These fetal lung vascular changes are reversed back to normal upon administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs), a regenerative approach previously shown to restore lung branching morphogenesis and epithelial differentiation in CDH models. Exploring pathways that are dysregulated in CDH lungs and involved in mechanotransduction, we found that compressed fetal lungs had altered expression of Hippo signaling factors that was restored upon AFSC-EV administration. We found that AFSC-EV cargo contains some miRNAs involved in lung vascular development and Hippo pathway, indicating that AFSC-EV regenerative effects is associated with the delivery of specific miRNAs. This study uncovers the role of mechanical compression that herniated organs exert on CDH fetal lungs and proposes a new cell-free strategy to restore normal fetal lung vascular development.

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“…Importantly, EVs released from PVECs under hypoxic conditions have been shown to have higher expression of miR‐210‐3p (a well‐known pro‐proliferative miRNA), and miR‐212‐5p (a recently identified anti‐proliferative miRNA) and to induce PASMC proliferation, pulmonary vascular remodelling and PH in mice (Chen et al., 2022b ). Dr. Chen shared published and unpublished findings to show how endogenous cell‐derived EVs carrying either miR‐212‐5p mimetics or miR‐210‐3p antagonists can be engineered to test their potency in treating PH in rodent models (Chen et al., 2022a ). She demonstrated how this can be achieved using a lentiviral system to express miR‐212‐5p or antagonists against miR‐210‐3p with an EV‐sorting sequence (GGAG) at the 3′‐end to direct them into endogenous EVs prior to their release from PVECs.…”

Section: Engineering the Cargo Of Evs For Treating Hlbs Diseasesmentioning

confidence: 99%

Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases

Chen

Dahlman

et al. 2023

J of Extracellular Vesicle

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Extracellular vesicles (EVs) carry diverse bioactive components including nucleic acids, proteins, lipids and metabolites that play versatile roles in intercellular and interorgan communication. The capability to modulate their stability, tissue‐specific targeting and cargo render EVs as promising nanotherapeutics for treating heart, lung, blood and sleep (HLBS) diseases. However, current limitations in large‐scale manufacturing of therapeutic‐grade EVs, and knowledge gaps in EV biogenesis and heterogeneity pose significant challenges in their clinical application as diagnostics or therapeutics for HLBS diseases. To address these challenges, a strategic workshop with multidisciplinary experts in EV biology and U.S. Food and Drug Administration (USFDA) officials was convened by the National Heart, Lung and Blood Institute. The presentations and discussions were focused on summarizing the current state of science and technology for engineering therapeutic EVs for HLBS diseases, identifying critical knowledge gaps and regulatory challenges and suggesting potential solutions to promulgate translation of therapeutic EVs to the clinic. Benchmarks to meet the critical quality attributes set by the USFDA for other cell‐based therapeutics were discussed. Development of novel strategies and approaches for scaling‐up EV production and the quality control/quality analysis (QC/QA) of EV‐based therapeutics were recognized as the necessary milestones for future investigations.

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MicroRNA-212-5p, an anti-proliferative miRNA, attenuates hypoxia and sugen/hypoxia-induced pulmonary hypertension in rodents

Cited by 11 publications

References 42 publications

LINC00599 influences smoke-related chronic obstructive pulmonary disease and regulates CSE-induced epithelial cell apoptosis and inflammation by targeting miR-212-5p/BASP1 axis

LINC00599 influences smoke-related chronic obstructive pulmonary disease and regulates CSE-induced epithelial cell apoptosis and inflammation by targeting miR-212-5p/BASP1 axis

Fetal lung vascular development is disrupted by mechanical compression and rescued by administration of amniotic fluid stem cell extracellular vesicles via regulation of the Hippo signaling pathway

Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases

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