Long-term exposure to high glucose induces vascular endothelial inflammation that can result in cardiovascular disease. Astragaloside IV (As-IV) is widely used for anti-inflammatory treatment of cardiovascular diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of As-IV on high glucose-induced endothelial inflammation and explored its possible mechanisms. In vivo, As-IV (40 and 80 mg/kg/d) was orally administered to rats for 8 weeks after a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33 mM glucose) in the presence or absence of As-IV, NPS2143 (CaSR inhibitor), BAY 11-7082 (NF-κB p65 inhibitor), and INF39 (NLRP3 inhibitor), and overexpression of CaSR was induced by infection of CaSR-overexpressing lentiviral vectors to further discuss the anti-inflammatory property of As-IV. The results showed that high glucose increased the expression of interleukin-18 (IL-18), interleukin-1β (IL-1β), NLRP3, caspase-1, and ASC, as well as the protein level of TLR4, nucleus p65, and CaSR. As-IV can reverse these changes in vivo and in vitro. Meanwhile, NPS2143, BAY 11-7082, and INF39 could significantly abolish the high glucose-enhanced NLRP3, ASC, caspase-1, IL-18, and IL-1β expression in vitro. In addition, both NPS2143 and BAY 11-7082 attenuated high glucose-induced upregulation of NLRP3, ASC, caspase-1, IL-18, and IL-1β expression. In conclusion, this study suggested that As-IV could inhibit high glucose-induced NLRP3 inflammasome activation and subsequent secretion of proinflammatory cytokines via inhibiting TLR4/NF-κB signaling pathway and CaSR, which provides new insights into the anti-inflammatory activity of As-IV.

Pulmonary arterial hypertension (PAH) is a chronic obstructive disease characterized by vascular remodeling. Studies have confirmed that ginsenoside Rg1 can improve pulmonary hypertension to a certain extent, but the potential mechanism by which it improves hypoxia-induced PAH remains unclear. The aim of this study was to investigate the therapeutic effect of ginsenoside Rg1 on hypoxia-induced PAH. The results showed that hypoxia promoted inflammation, EndMT, and vascular remodeling, which were accompanied by decreased CCN1 levels and increased p-NFκB p65, TGF-β1, and p-Smad 2/3 levels. Treatment with ginsenoside Rg1, recombinant CCN1, BAY-11-7082, and SB-431542 could prevent hypoxia-induced vascular remodeling, reduce the expression of the hypoxia-induced inflammatory cytokines TNF-α and IL-1β, inhibit the expression of the mesenchymal markers α-SMA and Vimentin and restore the expression of the endothelial markers CD31 and VE-cadherin to improve hypoxia-induced EndMT, which may be associated with the upregulation of CCN1 protein expression and downregulation of p-NFκB p65, TGF-β1, and p-Smad 2/3 in rats and cells. siRNA CCN1 transfection increased the expression of p-NFκB p65, TGF-β1, and p-Smad 2/3 and accelerated the occurrence and development of inflammation and EndMT after hypoxia. In summary, our study indicated that hypoxia-induced EndMT and inflammation play a role in hypoxic pulmonary hypertension (HPH). Ginsenoside Rg1 treatment could reverse hypoxia-induced EndMT and inflammation by regulating CCN1 and has potential value in the prevention and treatment of HPH.

Calpain‐1, a calcium‐activated neutral cysteine proteases, has been reported to be involved in the formation of pulmonary hypertension. HIF‐1α, an oxygen‐sensitive transcription factor, has been reported to activate genes involved in cell proliferation and extracellular matrix recombination. This study was designed to investigate the effect of calpain‐1 in hypoxic pulmonary hypertension (HPH) and to explore whether there is a relationship between calpain‐1 and HIF‐1α in this disease. In the hypoxia‐induced model of HPH, we found that hypoxia resulted in increased right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodelling and collagen deposition in lung tissues of mice. The levels of calpain‐1 and HIF‐1α were up‐regulated in the lung tissues of hypoxia‐treated mice and pulmonary arterial smooth muscle cells (PASMCs). Knock‐out of calpain‐1 restrained haemodynamic and histological changes induced by chronic hypoxia in mice, and inhibition of calpain‐1 also repressed the abnormal proliferation and migration of PASMCs. Besides, knock‐out or inhibition of calpain‐1 suppressed hypoxia‐induced expression of HIF‐1α, VEGF, PCNA, TGF‐β1, MMP2 and collagen I in vivo and in vitro. While inhibition of HIF‐1α abolished the above effects of calpain‐1. Furthermore, we found that calpain‐1 mediates the expression of HIF‐1α through NF‐κB (P65) under hypoxia conditions. In conclusion, our results suggest that calpain‐1 plays a pivotal role in hypoxia‐induced pulmonary vascular remodelling and fibrosis through HIF‐1α, providing a better understanding of the pathogenesis of HPH.

Inflammation eventually leads to pulmonary arterial hypertension (PAH). Astragaloside IV(AS‐IV) has a protective effect on pulmonary hypertension, but the specific protective mechanism has been unclear until now. Therefore, in this study, our aim was to investigate the mechanisms underlying the effects of AS‐IV on PAH. In vivo, male Sprague‐Dawley (SD) rats were injected intraperitoneally with monocrotaline (MCT, 60 mg/kg) and treated with AS‐IV (40 mg/kg, 80 mg/kg), MCC950 and MDL‐28170. In vitro, human pulmonary artery endothelial cells (HPAECs) were treated with monocrotaline pyrrole (MCTP, 60 μg/mL). The protein expression levels of NLRP‐3, caspase‐1, ASC, IL‐18, IL‐1β and calpain‐1 were measured in vivo and/or in vitro. The results showed that AS‐IV decreased the protein expression levels of NLRP‐3, caspase‐1, ASC, IL‐18, IL‐1β and calpain‐1 in vivo and/or vitro. In conclusion, in this study the results suggested that AS‐IV could inhibit monocrotaline‐induced pulmonary arterial hypertension via the NLRP‐3/calpain‐1 pathway.