miR-182-3p/Myadm contribute to pulmonary artery hypertension vascular remodeling via a KLF4/p21-dependent mechanism

Sun, Lan; Lin, Peirong; Chen, Ying; Yu, Haoying; Ren, Shen; Wang, Jingrong; Zhao, Lei; Du, Guanhua

doi:10.7150/thno.44687

Cited by 42 publications

(46 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other researchers 11 have shown that miR-17-5p plays a part in PAH and the proliferation of PASMCs by regulating p21. A latest report 35 indicated that miR-182-3p can regulate pulmonary hypertension vascular remodeling and proliferation of PASMCs through KLF4/p21-dependent mechanism, which is consistent with our findings. However, based on the complex occurrence and development of diseases, whether there is an interaction network between miR-193-3p and other miRNAs such as miR-182-3p and miR-17-5p in PAH vascular remodeling should be further explored by future studies.…”

Section: Discussionsupporting

confidence: 93%

MiR‐193‐3p attenuates the vascular remodeling in pulmonary arterial hypertension by targeting PAK4

et al. 2020

Pulm. circ.

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease associated with dysfunction of pulmonary artery endothelial cells (PAEC) and pulmonary artery smooth muscle cells (PASMC). To explore the potential mechanism of miR-193-3p in PAH, human PASMCs and rats were respectively stimulated by hypoxia and monocrotaline (MCT) to establish PAH model in vivo and in vitro. The expressions of miR-193-3p and PAK4 in the lung samples of PAH patients and paired healthy samples from the healthy subjects, in PHA cells and rats were detected by qRT-PCR. The pathological features of lung tissues were determined using HE staining. The binding relationship between miR-193-3p and PAK4 was analyzed by TargetScan and verified by luciferase reporter assay. Cell viability, apoptosis, migration were detected by MTT, flow cytometry and wound healing assays, respectively. The protein expressions of PAK4, PCNA, P21, p-AKT and AKT in vivo or in vitro were determined by Western blot. In this study, we found that in PAH, miR-193-3p expression was downregulated and PAK4 expression was up-regulated. MiR-193-3p directly targeted PAK4 and negatively regulated its expression. Hypoxia induction promoted cell proliferation, migration and apoptosis resistance accompanied with increased the expressions of PCNA and p-AKT/AKT and decreased that of P21 in PASMCs. MCT treatment increased p-AKT/AKT and decreased P21 expression, and caused pulmonary vascular remodeling in the model rats. MiR-193-3p overexpression attenuated pulmonary vascular remodeling, decreased p-AKT/AKT and increased P21 levels via downregulating PAK4 in MCT-induced rats. The results in this study demonstrated that upregulation of miR-193-3p reduced cell proliferation, migration, and apoptosis of PAH in vitro and pulmonary vascular remodeling in PAH in vivo through downregualting PAK4.

show abstract

Section: Discussionsupporting

confidence: 93%

MiR‐193‐3p attenuates the vascular remodeling in pulmonary arterial hypertension by targeting PAK4

et al. 2020

Pulm. circ.

View full text Add to dashboard Cite

show abstract

“…It has been well known that the contractile phenotype of VSMCs is maintained by activating a subset of SRF-dependent genes encoding contractile and cytoskeletal proteins, and that KLF4 behaves as a repressor of VSMC differentiation, inhibiting these gene expression 31 - 33 . The above findings suggested that Sal-miR-1 and 3-regulated OTUD7B/KLF4/NMHC IIA pathway modulates VSMC migration and adhesion, which are fundamental characteristics of the proliferative phenotype.…”

Section: Resultsmentioning

confidence: 99%

“…VSMC contractile gene expression and, thus differentiation, is under direct transcriptional control by SRF and cofactors, such as myocardin and myocardin-related transcription factors (MRTFs), which act as powerful transcriptional coactivators of SRF in mammalian cells. On the other hand, KLF4 functions as a repressor of VSMC differentiation, inhibiting the expression of SMC differentiation markers such as SM α-actin, SM22α, and SMMHC 31 - 33 . Previous studies have indicated that the underlying mechanisms of the downregulation of VSMC differentiation markers (e.g.…”

Section: Discussionmentioning

confidence: 99%

Salvia miltiorrhiza-derived miRNAs suppress vascular remodeling through regulating OTUD7B/KLF4/NMHC IIA axis

et al. 2020

View full text Add to dashboard Cite

Objective: Abnormal proliferation and migration of vascular smooth muscle cells ( VSMCs) are essential for vascular remodeling. Natural compounds with diterpene chinone or phenolic acid structure from Salvia miltiorrhiza, an eminent medicinal herb widely used to treat cardiovascular diseases in China, can effectively attenuate vascular remodeling induced by vascular injury. However, it remains unknown whether Salvia miltiorrhiza -derived miRNAs can protect VSMCs from injury by environmental stimuli. Here, we explored the role and underlying mechanisms of Salvia miltiorrhiza -derived Sal-miR-1 and 3 in the regulation of VSMC migration and monocyte adhesion to VSMCs induced by thrombin. Methods: A mouse model for intimal hyperplasia was established by the ligation of carotid artery and the injured carotid arteries were in situ-transfected with Sal-miR-1 and 3 using F-127 pluronic gel. The vascular protective effects of Sal-miR-1 and 3 were assessed via analysis of intimal hyperplasia with pathological morphology. VSMC migration and adhesion were analyzed by the wound healing, transwell membrane assays, and time-lapse imaging experiment. Using loss- and gain-of-function approaches, Sal-miR-1 and 3 regulation of OTUD7B/KLF4/NMHC IIA axis was investigated by using luciferase assay, co-immunoprecipitation, chromatin immunoprecipitation, western blotting, etc. Results: Salvia miltiorrhiza- derived Sal-miR-1 and 3 can enter the mouse body after intragastric administration, and significantly suppress intimal hyperplasia induced by carotid artery ligation. In cultured VSMCs, these two miRNAs inhibit thrombin-induced the migration of VSMCs and monocyte adhesion to VSMCs. Mechanistically, Sal-miR-1 and 3 abrogate OTUD7B upregulation by thrombin via binding to the different sites of the OTUD7B 3'UTR. Most importantly, OTUD7B downregulation by Sal-miR-1 and 3 attenuates KLF4 protein levels via decreasing its deubiquitylation, whereas decreased KLF4 relieves its repression of transcription of NMHC IIA gene and thus increases NMHC IIA expression levels. Further, increased NMHC IIA represses VSMC migration and monocyte adhesion to VSMCs via maintaining the contractile phenotype of VSMCs. Conclusions: Our studies not only found the novel bioactive components from Salvia miltiorrhiza but also clarified the molecular mechanism underlying Sal-miR-1 and 3 inhibition of VSMC migration and monocyte adhesion to VSMCs. These results add important knowledge to the pharmacological actions and bioactive components of Salvia miltiorrhiza . Sal-miR-1 and 3-regulated OTUD7B/KLF4/NMHC IIA axis may represent a therapeutic target for vascular remodeling.

show abstract

“…Pulmonary arterial hypertension (PAH) is a fatal disease associated with the vascular cell dysfunction, hyperproliferation and infiltration of inflammatory macrophages 1 , 2 . Growing evidence has implicated that mitochondria were involved in the pathogenic mechanism of PAH 3 - 5 .…”

Section: Introductionmentioning

confidence: 99%

Cannabidiol attenuates pulmonary arterial hypertension by improving vascular smooth muscle cells mitochondrial function

et al. 2021

View full text Add to dashboard Cite

Rationale: Pulmonary arterial hypertension (PAH) is a chronic disease associated with enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional mitochondria, and the clinical therapeutic option for PAH is very limited. Recent studies showed that cannabidiol (CBD), a non-psychoactive constituent of cannabinoids, possessed antioxidant effect towards several cardiovascular diseases, whereas the mechanistic effect of CBD in PAH is unknown. Methods: In this study, the effects of CBD in PAH were determined by analyzing its preventive and therapeutic actions in PAH rodent models in vivo and PASMCs' proliferation test in vitro. Additionally, CBD's roles in mitochondrial function and oxidant stress were also assessed in PASMCs. Results: We found that CBD reversed the pathological changes observed in both Sugen-hypoxia and monocrotaline-induced PAH rodent models in a cannabinoid receptors-independent manner. Our results also demonstrated that CBD significantly inhibited the PASMCs' proliferation in PAH mice with less inflammation and reactive oxygen species levels. Moreover, CBD alleviated rodent PAH by recovering mitochondrial energy metabolism, normalizing the hypoxia-induced oxidant stress, reducing the lactate overaccumulation and abnormal glycolysis. Conclusions: Taken together, these findings confirm an important role for CBD in PAH pathobiology.

show abstract

miR-182-3p/Myadm contribute to pulmonary artery hypertension vascular remodeling via a KLF4/p21-dependent mechanism

Cited by 42 publications

References 41 publications

MiR‐193‐3p attenuates the vascular remodeling in pulmonary arterial hypertension by targeting PAK4

MiR‐193‐3p attenuates the vascular remodeling in pulmonary arterial hypertension by targeting PAK4

Salvia miltiorrhiza-derived miRNAs suppress vascular remodeling through regulating OTUD7B/KLF4/NMHC IIA axis

Cannabidiol attenuates pulmonary arterial hypertension by improving vascular smooth muscle cells mitochondrial function

Contact Info

Product

Resources

About