Protective effects of isorhamnetin on pulmonary arterial hypertension: in vivo and in vitro studies

Abstract

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.

Effects of Isorhamnetin on Diabetes and Its Associated Complications: A Review of In Vitro and In Vivo Studies and a Post Hoc Transcriptome Analysis of Involved Molecular Pathways

“…Additionally, it may ameliorate acute kidney injury by inhibiting the NF-κB signaling pathway activation [ 31 ]. Additionally, isorhamnetin exhibits anti-thrombus [ 77 ], antihypertensive [ 78 ], anti-inflammatory [ 26 ], anti-osteoporosis [ 79 ], antiplatelet activity [ 80 ], hepatoprotective [ 81 ], and anti-hypoxia [ 82 ] effects. It has also been shown that isorhamnetin could boost innate immunity [ 83 ].…”

Traditional Herbal Medicine Discovery for the Treatment and Prevention of Pulmonary Arterial Hypertension

“…The epidemiological studies indicated that the progress of PAH was prevented with various sourced flavonoids such as curcumin ( Rice et al, 2016 ), isoliquiritigenin ( Jin et al, 2019 ), isorhamnetin ( Chang et al, 2020 ), naringenin ( Ahmed et al, 2014 ), rulin ( Li et al, 2014 ), chrysin ( Li XW. et al, 2015 ), silibinin ( Zhang T. et al, 2020 ), formononetin ( Cai et al, 2019 ), apigenin ( He et al, 2020 ), and isoquercitrin ( Zhang Y. et al, 2017 ).…”

“…et al, 2015 ), silibinin ( Zhang T. et al, 2020 ), formononetin ( Cai et al, 2019 ), apigenin ( He et al, 2020 ), and isoquercitrin ( Zhang Y. et al, 2017 ). When treated with the flavonoid of curcumin, isoliquiritigenin, isorhamnetin, or naringenin, hypoxia- or MCT-induced PAH rodents were significantly protected, with changes in inhibited inflammatory markers such as TNF-α, IL-1β, IL-6 ( Ahmed et al, 2014 ; Rice et al, 2016 ; Jin et al, 2019 ; Zhang T. et al, 2020 ; Chang et al, 2020 ), and BMP signaling ( Chang et al, 2020 ). Interestingly, the oxidative stress levels in PAH rodents, including decreased ROS and elevation of NOX4, were alleviated by treatment of naringenin, rulin, and chrysin ( Ahmed et al, 2014 ; Li et al, 2014 ; Li XW.…”

Isorhamnetin Ameliorates Aspergillus fumigatus Keratitis by Reducing Fungal Load, Inhibiting Pattern-Recognition Receptors and Inflammatory Cytokines

“…Isorhamnetin (3,5,7-trihydroxy-2-[4-hydroxy-3-methoxyphenyl] chromen-4-one) is an important natural flavonoid extracted from the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L. 6,7 To date, numerous investigations revealed that isorhamnetin has extensive pharmacological activities and biological effects, such as anti-inflammation, 8 antimicrobial, 9,10 cardiovascular and cerebrovascular protection, 11,12 antitumor, 13 and antioxidation. [14][15][16] For example, isorhamnetin could increase pathogen cell membrane permeability by generating oxidative species in a dose-dependent manner, 17 thus exhibiting antifungal activity on Aspergillus niger, Fusarium sporotrichum, and Candida albicans in vitro. 18 But whether isorhamnetin effects the growth of Aspergillus fumigatus, one of the most common fungal pathogens for FK, remains unknown.…”

“…8 Isorhamnetin exerts protective effects on lipopolysaccharide (LPS)-induced acute lung injury in mice by inhibiting the expression of cyclooxygenase-2. 15 It also suppresses LPSmediated inflammatory response in BV2 microglia through inhibiting the nuclear factor (NF)-κB signaling pathway, downregulating Toll-like receptor 4 (TLR4) and eliminating reactive oxygen species accumulation. 21 In addition, the antituberculosis property of isorhamnetin has been reported in murine model via repressing the expression of proinflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-12.…”