The Notch signaling pathway participates in pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis. Astragaloside IV (AS-IV) is an effective antiproliferative treatment for vascular diseases. The present study aimed to investigate the protective effects and mechanisms underlying AS-IV on hypoxia-induced PASMC proliferation and pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) model rats. Rats were divided into the following four groups: i) normoxia; ii) hypoxia (10% O 2); iii) treatment, hypoxia + intragastrical administration of AS-IV (2 mg/kg) daily for 28 days; and iv) DAPT, hypoxia + AS-IV treatment + subcutaneous administration of DAPT (10 mg/kg) three times daily. The effects of AS-IV treatment on the development of hypoxia-induced PAH, right ventricle (RV) hypertrophy and pulmonary vascular remodeling were examined. Furthermore, PASMCs were treated with 20 µmol/l AS-IV under hypoxic conditions for 48 h. To determine the effect of Notch signaling in vascular remodeling and the potential mechanisms underlying AS-IV treatment, 5 mmol/l γ-secretase inhibitor [N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT)] was used. Cell viability and apoptosis were determined by performing the MTT assay and flow cytometry, respectively. Immunohistochemistry was conducted to detect the expression of proliferating cell nuclear antigen (PCNA). Moreover, the mRNA and protein expression levels of Notch-3, Jagged-1, hes family bHLH transcription factor 5 (Hes-5) and PCNA were measured via reverse transcription-quantitative PCR and western blotting, respectively. Compared with the normoxic group, hypoxia-induced PAH model rats displayed characteristics of PAH and RV hypertrophy, whereas AS-IV treatment alleviated PAH and prevented RV hypertrophy. AS-IV also inhibited hypoxia-induced pulmonary vascular remodeling, as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia-induced PAH model rats. Compared with normoxia, hypoxia promoted PASMC proliferation in vitro, whereas AS-IV treatment inhibited hypoxia-induced PASMC proliferation by downregulating PCNA expression in vitro and in vivo. In hypoxia-treated PAH model rats and cultured PASMCs, AS-IV treatment reduced the expression levels of Jagged-1, Notch-3 and Hes-5. Furthermore, Notch signaling inhibition via DAPT significantly inhibited the pulmonary vascular remodeling effect of AS-IV in vitro and in vivo. Collectively, the results indicated that AS-IV effectively reversed hypoxia-induced pulmonary vascular remodeling and PASMC proliferation via the Notch signaling pathway. Therefore, the present study provided novel insights into the mechanism underlying the use of AS-IV for treatment of vascular diseases, such as PAH.
Background Both experimental and clinical studies have revealed satisfactory effects with the traditional Chinese formula Pinggan Qianyang decoction (PGQYD) for improving vascular remodeling caused by essential hypertension. The present study explored various therapeutic targets of PGQYD using mRNA transcriptomics. Methods In this study, rats were randomly divided into three groups: Wistar-Kyoto (WKY; normal control), spontaneously hypertensive (SHR), and PGQYD-treated rat groups. After 12 weeks of PGQYD treatment, behavioral tests were employed and the morphology of thoracic aortas were examined with hematoxylin–eosin (HE) and Masson staining and electron microscopy. The mRNA expression profiles were identified with RNA-Seq and quantitative real-time PCR to validate changes in gene expression observed with microarray analysis. The gene ontology and pathway enrichment analyses were carried out to predict gene function and gene co-expressions. Pathway networks were constructed to identify the hub biomarkers, which were further validated by western blotting and immunofluorescence analysis. Results After PGQYD treatment, the behavioral tests and histological and morphological findings of vascular remodeling were obviously meliorated compared with the SHR group. In the rat thoracic aorta tissues, 626 mRNAs with an exact match were identified. A total of 129 of mRNAs (fold change > 1.3 and P-value < 0.05) were significantly changed in the SHR group compared to the WKY group. Among them, 16 mRNAs were markedly regulated by PGQYD treatment and validated with quantitative real-time PCR. Additionally, target prediction and bioinformatics analyses revealed that these mRNAs could play therapeutic roles through biological processes for regulating cell metabolic processes (such as glycation biology), biological adhesions, rhythmic processes, and cell autophagy. The cellular signaling pathways involved in autophagy may be AGE–RAGE/PI3K/Akt/mTOR signaling pathway. Conclusion The present study provides novel insights for future investigations to explore the mechanisms by which PGQYD may effectively inhibit vascular remodeling by activating the AGE–RAGE/PI3K/Akt/mTOR signal pathway in cell autophagy biology.
Subsequently to the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 4A on p. 6, the 'T' and 'DAPT' data panels appeared to contain some of the same data, although one of the panels appeared to have been rotated through 180° relative to the other.
Age-related functional decline is a physiological phenomenon that occurs in all organ systems. However, the acceleration and early occurrence of this process are observed in cardiovascular pathologies, including hypertension. This study aimed to investigate SIRT1–PTEN signaling in aortic tissue from spontaneously hypertensive rats (SHRs) and changes in SIRT1 and PTEN expression following treatment with Pinggan-Qianyang decoction (PGQYD) and explore the mechanism involved in the treatment of hypertensive vascular aging with traditional Chinese medicine. In this study, we used two rat models: spontaneously hypertensive rats (SHRs) at 14 and 64 weeks of age and WKY rats at 64 weeks of age. The degree of irritability and rotation tolerance time were evaluated to determine the effects of PGQYD on animal behavior. The morphology of the thoracic aorta was examined by hematoxylin-eosin (HE) and Masson staining and electron microscopy. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and superoxide dismutase (SOD) and anti-superoxide anion content were detected. Senescence-associated β-galactosidase (SA-β-Gal) staining was used to observe the thoracic aorta during vascular aging. RT-qPCR, immunofluorescence, and Western blot analysis were performed to detect changes in the mRNA and protein expression of p53, p21, SIRT1, and PTEN in rat aortic tissues. Behavioral tests and histological and morphological analyses showed the remarkable amelioration of vascular aging after PGQYD treatment compared with that in the older SHRs. Moreover, PGQYD significantly decreased vascular aging in SHRs, as indicated by reduced SA-β-Gal staining, NADPH oxidase activity, and p53 and p21 expression, and increased anti-superoxide anion and SOD content. Furthermore, PGQYD increased SIRT1 and PTEN expression, but the downregulated expression of SIRT1 induced by a SIRT1 inhibitor abolished the PGQYD-induced antiaging effects on gene expression and antioxidant activity and enhanced PTEN expression. PGQYD could ameliorate vascular aging effects in SHRs, which may have been mediated via the regulation of SIRT1–PTEN signaling in aortic tissue.
Background: Both experimental and clinical studies have revealed satisfactory effects with the traditional Chinese formula Pinggan Qianyang decoction (PGQYD) for improving vascular remodeling caused by essential hypertension. The present study explored various therapeutic targets of PGQYD using mRNA transcriptomics. Methods: In this study, rats were randomly divided into three groups: Wistar-Kyoto (WKY; normal control), spontaneously hypertensive (SHR), and PGQYD-treated rat groups. After 12 weeks of PGQYD treatment, behavioral tests were employed and the morphology of thoracic aortas were examined with hematoxylin-eosin (HE) and Masson staining and electron microscopy. The mRNA expression profiles were identified with RNA-Seq and quantitative real-time PCR to validate changes in gene expression observed with microarray analysis. The gene ontology and pathway enrichment analyses were carried out to predict gene function and gene co-expressions. Pathway networks were constructed to identify the hub biomarkers, which were further validated by western blotting and immunofluorescence analysis. Results: After PGQYD treatment, the behavioral tests and histological and morphological findings of vascular remodeling were obviously meliorated compared with the SHR group. In the rat thoracic aorta tissues, 626 mRNAs with an exact match were identified. A total of 129 of mRNAs (fold change >1.3 and P-value <0.05) were significantly changed in the SHR group compared to the WKY group. Among them, 16 mRNAs were markedly regulated by PGQYD treatment and validated with quantitative real-time PCR. Additionally, target prediction and bioinformatics analyses revealed that these mRNAs could play therapeutic roles through biological processes for regulating cell metabolic processes (such as glycation biology), biological adhesions, rhythmic processes, and cell aggregation. The cellular signaling pathways involved in glycosylation may be AGE-RAGE signaling pathway.Conclusion: The present study provides novel insights for future investigations to explore the mechanisms by which PGQYD may effectively inhibit vascular remodeling by activating the AGE-RAGE signal pathway in glycation biology.
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