Pulmonary arterial hypertension (PAH) is a malignant disease with high mortality and closely involves the bone morphogenetic protein (BMP) pathway. Mutations in BMPR2 caused proliferation of pulmonary artery smooth muscle cells (PASMCs) leading to PAH. Isorhamnetin, one of the main naturally occurring flavonoids extracted from Hippophae rhamnoides L, shows antiinflammatory and anti-proliferative properties. Nevertheless, the effects of isorhamnetin on PAH remain unclear. This study aimed to investigate whether isorhamnetin has protective effects against PAH and explore possible mechanisms. An in vivo model of PAH induced by monocrotaline (MCT) was employed, and sildenafil and isorhamnetin were orally administered for 21 consecutive days. An in vitro model induced by TNF-α was employed, and cell proliferation of HPASMCs was detected. Results indicated that isorhamnetin significantly improved hemodynamic, histopathological, and echocardiographic changes in MCT-induced PAH in rats. In vitro, isorhamnetin suppressed TNF-α-induced HPASMCs proliferation. Furthermore, isorhamnetin improved protein expression of BMPR2 and suppressed protein expression of TNF-α and IL-6 in rat lungs. Isorhamnetin improved protein expression of BMPR2 and p-smad1/5 and mRNA expression of Id1 and Id3 in HPASMCs. Isorhamnetin ameliorated MCT-induced PAH in rats and inhibited TNF-α-induced HPASMCs proliferation by a mechanism likely involving the regulation of the BMP signaling pathway.

BackgroundSeveral studies have indicated an association between tumor necrosis factor-alpha (TNF-α) or interleukin (IL)-6 gene polymorphisms and lung cancer risk. However, the conclusions remain controversial.MethodsAn English literature screening about case-control trials with regard to TNF-α (-308G/A) or IL-6 (174G/C) polymorphisms and lung cancer susceptibility was performed on PubMed, EMBASE, and EBSCO until November 2012. The pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated using STATA 11.0. Sensitivity analysis was performed by sequential omission of individual studies. Publication bias was evaluated by Egger’s linear regression test and funnel plots.ResultsEight eligible studies, including 1,690 patients and 1,974 controls, were identified in this meta-analysis. Compared with the control, no significant association was revealed between TNF-α-308G/A (GG + GC vs. CC: OR = 1.10, 95% CI: 0.73 to 1.64; GG vs. GC + CC: OR = 1.02, 95% CI: 0.81 to 1.27; GC vs. CC: OR = 1.13, 95% CI: 0.73 to 1.77; GG vs. CC: OR = 1.04, 95% CI: 0.80 to 1.36; G vs. C: OR = 1.03, 95% CI: 0.90 to 1.18) or IL-6 174G/C (GG + GC vs. CC: OR = 1.10, 95% CI: 0.73 to 1.64; GG vs. GC + CC: OR = 1.02, 95% CI: 0.81 to 1.27; GC vs. CC: OR = 1.13, 95% CI: 0.73 to 1.77; GG vs. CC: OR = 1.04, 95% CI: 0.80 to 1.36; G vs. C: OR = 1.03, 95% CI: 0.90 to 1.18) and lung cancer risk. The pooled OR remained unchanged after removing the maximum-weight study and no publication bias was observed.ConclusionsThe study raises the possibility of no correlation between the polymorphisms of the two genes and lung cancer susceptibility. However, further researches with large-sample or subgroup analyses are necessary to validate the conclusions.

DISCLAIMER This paper was submitted to the Bulletin of the World Health Organization and was posted to the COVID-19 open site, according to the protocol for public health emergencies for international concern as described in Vasee Moorthy et al.

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