Abstract
Pulmonary hypertension (PH) is characterized by vascular remodeling caused by marked proliferation of pulmonary artery smooth muscle cells (PASMCs). Andrographolide (ANDRO) is a potent anti-inflammatory agent which possesses antioxidant, and has anticarcinogenic activity. The present study examined potential therapeutic effects of ANDRO on PH in both chronic hypoxia and Sugen5416/hypoxia mouse PH models. Effects of ANDRO were also studied in cultured human PASMCs isolated from either healthy donors or PH patients. In vivo, ANDRO decreased distal pulmonary arteries (PAs) remodeling, mean PA pressure and right ventricular hypertrophy in chronic hypoxia- and Sugen/hypoxia-induced PH in mice. ANDRO reduced cell viability, proliferation and migration, but increased cell apoptosis in the PASMCs isolated from PH patients. ANDRO also reversed the dysfunctional bone morphogenetic protein receptor type-2 (BMPR2) signaling, suppressed [Ca2+]i elevation, reactive oxygen species (ROS) generation, and the upregulated expression of IL-6 and IL-8, ET-1 and VEGF in PASMCs from PH patients. Moreover, ANDRO significantly attenuated the activation of TLR4/NF-κB, ERK- and JNK-MAPK signaling pathways and reversed the inhibition of p38-MAPK in PASMCs of PH patients. Further, ANDRO blocked hypoxia-triggered ROS generation by suppressing NADPH oxidase (NOX) activation and augmenting nuclear factor erythroid 2-related factor 2 (Nrf2) expression both in vitro and in vivo. Conventional pulmonary vasodilators have limited efficacy for the treatment of severe PH. We demonstrated that ANDRO may reverse pulmonary vascular remodeling through modulation of NOX/Nrf2-mediated oxidative stress and NF-κB-mediated inflammation. Our findings suggest that ANDRO may have therapeutic value in the treatment of PH.
Highlights
Since the TLR4/NF-κB pathway is important in the development of Pulmonary hypertension (PH), we investigated the involvement of this pathway in the therapeutic effect of ANDRO
We studied the effect of ANDRO on the levels of IL-6 and IL-8, endothelin-1 and vascular endothelial growth factor (VEGF), all of which are important in pulmonary vascular remodeling
These results suggest that ANDRO attenuated PH-triggered reactive oxygen species (ROS) generation by inactivating NADPH oxidases and restoring nuclear factor erythroid 2-related factor 2 (Nrf2) expression in PH-pulmonary artery smooth muscle cells (PASMCs)
Summary
Biomolecules 2021, 11, 1801 along with adventitial fibroblast activation, cause the remodeling of the pulmonary vessels These events narrow the vascular lumen and cause pulmonary hypertension [2]. Emerging evidence indicates that PH may be considered as a proliferative disorder with a cancer-like nature and shares a large number of underlying pathogenic mechanisms with cancers [3] This offers exciting opportunities to employ certain cancer-specific therapeutic strategies as well as anti-cancer agents for the treatment of PH [4]. The activation of the NF-κB signaling pathway governs the transcription of pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-1β [14,15,16]. Considering the complex crosstalk between these two events, a therapeutic agent with both anti-inflammatory and antioxidant activities is promising for the treatment of human PH
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