Abstract
BackgroundPulmonary hypertension (PH) remains a prevalent disease globally. Sodium tanshinone II sulfonate A (STS) has been used in clinical treatment of PH.AimsThe aim of the present study was to investigate the effect of sodium STS treatment on hypoxia-induced PH and related mechanisms.MethodsMale Sprague-Dawley rats were housed in a hypoxic chamber with an oxygen concentration of 10 ± 1% for 8 h a day over 21 days. Rats were treated with either STS (low-dose: 10 mg/kg or high-dose: 30 mg/kg) or LY294002 (which is an inhibitor of PI3K). Pulmonary arterial pressure (PAP) was measured, right ventricular hypertrophy parameters were monitored, lung edema parameters were measured, and pathological changes were observed by hematoxylin-eosin (HE) staining. Protein expressions of apoptosis, and PI3K/AKT/mTOR/autophagy pathways in rat lung tissue were examined by western blot. Levels of the pro-inflammatory factors IL-6, IL-8, TNF-α in lung tissues of rats were measured using an enzyme linked immunosorbent assay (ELISA).ResultsResults of our study demonstrate that persistent exposure to hypoxic conditions increased PAP, right ventricular hypertrophy, lung edema, parameters of lung vascular proliferation and decreased the ratio of Bax/Bcl-2. Furthermore, hypoxic conditions activated the PI3K/Akt/mTOR pathway, inhibited autophagy, and elevated abundance of inflammatory factors in rat lung tissue. Treatment with STS resulted in a dose-dependent decrease in PAP, right ventricular hypertrophy, lung edema, lung vascular proliferation and reversed hypoxia induced lung tissue protein expression and pro-inflammatory factors in rat lung tissue. In addition, hypoxia-induced increases in PAP, cardiac hypertrophy, and lung expression of the proteins PI3K/Akt/mTOR/autophagy pathway were partially reversed by treatment with LY294002.ConclusionsSTS alleviates hypoxia-induced PH by promoting apoptosis, inhibiting PI3K/AKT/mTOR pathway, up-regulating autophagy, and inhibiting inflammatory responses.
Highlights
Pulmonary hypertension (PH) is a disease of the lung which is characterized by increased pulmonary vascular resistance, vascular remodeling, and obstruction of the pulmonary arteries
Treatment with Sodium tanshinone II sulfonate A (STS) resulted in a dosedependent decrease in Pulmonary arterial pressure (PAP), right ventricular hypertrophy, lung edema, lung vascular proliferation and reversed hypoxia induced lung tissue protein expression and proinflammatory factors in rat lung tissue
Hypoxia-induced increases in PAP, cardiac hypertrophy, and lung expression of the proteins Phosphoinositide 3kinase (PI3K)/Akt/Mammalian target of rapamycin (mTOR)/autophagy pathway were partially reversed by treatment with LY294002
Summary
Pulmonary hypertension (PH) is a disease of the lung which is characterized by increased pulmonary vascular resistance, vascular remodeling, and obstruction of the pulmonary arteries. The World Health Organization (WHO) has classified PH into five groups on the basis of similarities in pathophysiology, clinical presentation, and therapeutic options: Group I: pulmonary arterial hypertension, Group II: pulmonary hypertension due to left heart disease, Group III: pulmonary hypertension due to lung disease and/or chronic hypoxia, Group IV: pulmonary hypertension due to blood clots in the lungs, Group V: pulmonary hypertension due to blood and other disorders (Simonneau et al, 2019). PH related secondary effects due to lung disease and/or chronic hypoxia is termed Class III PH and is the second most common cause of elevated pulmonary arterial pressure following heart disease (Strange et al, 2012; Lopez-Campos et al, 2016). Pulmonary vascular remodeling and vasoconstriction are the two main pathological features seen in patients presenting with group III PH. New therapeutic approaches which target changes in lung parenchyma, pulmonary vasculature remodeling, and vasoconstriction should be explored for their ability to improve clinical outcomes in patients presenting with Group III PH. Sodium tanshinone II sulfonate A (STS) has been used in clinical treatment of PH
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