Effects of sodium tanshinone II A sulphonate on hypoxic pulmonary hypertension in rats in vivo and on Kv2.1 expression in pulmonary artery smooth muscle cells in vitro

Huang, Yu-Fang; Liu, Manling; Dong, Minyue; Yang, Weichuan; Zhang, Bo; Luan, Li-li; Dong, Huijuan; Xu, Min; Wang, Yanxia; Liu, Li‐Li; Gao, Yuqi; Li, Zhichao

doi:10.1016/j.jep.2009.07.020

Cited by 27 publications

(31 citation statements)

References 32 publications

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“…We confirmed that intraperitoneal injection with STS attenuated pulmonary vascular resistance and remodeling in a rat CHPH model, which was indicated by decreased RV systolic pressure, RV hypertrophy, and medial wall thickening of small pulmonary vasculature. These results are consistent with previous reports (19). The dose of STS (10 mg/kg/d) used here to treat CHPH did not cause a detectable toxic effect, as evaluated by parameters including organ and body index.…”

Section: Discussionsupporting

confidence: 93%

“…STS has been clinically used in Asian countries for the prevention and treatment of coronary heart disease (18). Recent studies indicated that STS exerts protective effects on hypoxic pulmonary hypertension, including lowering pulmonary artery pressure and decreasing pulmonary artery thickness and right ventricular hypertrophy (19). These effects were suggested to be achieved partially through the regulation of intracellular Ca 21 homeostasis in pulmonary arterial smooth cells (PASMCs) (19,20); however, the underlying detailed mechanisms remain largely unclear and deserve further investigation.…”

Section: Abstract: Sts; Trpc; Soce; Pulmonary Hypertensionmentioning

confidence: 99%

“…Recent studies indicated that STS exerts protective effects on hypoxic pulmonary hypertension, including lowering pulmonary artery pressure and decreasing pulmonary artery thickness and right ventricular hypertrophy (19). These effects were suggested to be achieved partially through the regulation of intracellular Ca 21 homeostasis in pulmonary arterial smooth cells (PASMCs) (19,20); however, the underlying detailed mechanisms remain largely unclear and deserve further investigation. The elucidation of the involved mechanisms will serve as a rationale for the potential clinical application of STS or tanshinone IIA in PAH treatment, which could benefit thousands of patients with PAH by greatly reducing their medical expenses.…”

Section: Abstract: Sts; Trpc; Soce; Pulmonary Hypertensionmentioning

confidence: 99%

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Sodium Tanshinone IIA Sulfonate Inhibits Canonical Transient Receptor Potential Expression in Pulmonary Arterial Smooth Muscle from Pulmonary Hypertensive Rats

Wang

Qian

Wan

et al. 2013

Am J Respir Cell Mol Biol

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Danshen, the dried root of Salvia miltiorrhiza, is widely used in clinics in China for treating various diseases, including cardiovascular diseases. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA isolated as the major active component from Danshen, was recently reported to be effective in attenuating the characteristic pulmonary vascular changes associated with chronically hypoxic pulmonary hypertension (CHPH); however, the underlying detailed mechanisms are poorly understood. In this study, we investigated the effects of STS on basal intracellular Ca 21 concentration ([Ca 21 ] i ) and store-operated Ca 21 entry (SOCE) in distal pulmonary arterial smooth muscle cells (PASMCs) exposed to prolonged hypoxia or isolated from CHPH rats. SOCE measured by Mn 21 quenching of Fura-2 fluorescence in PASMCs from rats exposed to chronic hypoxia (10% O 2 , 21 d) was increased by 59%, and basal [Ca 21 ] i was increased by 119%; this effect was inhibited by intraperitoneal injection of STS. These inhibitory effects of STS on hypoxic increases of SOCE and basal [Ca 21 ] i were associated with reduced expression of canonical transient receptor potential (TRPC)1 and TRPC6 in distal pulmonary arterial smooth muscle and decreases on right ventricular pressure, right ventricular hypertrophy, and peripheral pulmonary vessel thickening. In ex vivo cultured distal PASMCs from normoxic rats, STS (0-25 mM) dose-dependently inhibited hypoxiainduced cell proliferation and migration, paralleled with attenuation in increases of basal [Ca 21 ] i , SOCE, mRNA, and protein expression of TRPC1 and TRPC6. STS also relieved right ventricular systolic pressure, right ventricular hypertrophy, and TRPC1 and TRPC6 protein expression in distal pulmonary arteries in a monocrotaline-induced rat model of pulmonary arterial hypertension. These results indicate that STS prevents pulmonary arterial hypertension development likely by inhibiting TRPC1 and TRPC6 expression, resulting in normalized basal [Ca 21 ] i and attenuated proliferation and migration of PASMCs.Keywords: STS; TRPC; SOCE; pulmonary hypertension Pulmonary arterial hypertension (PAH) is a rare yet life-threatening disease that affects 15 per 1 million adults, according to the most recent estimation in 2008 (1). It is physiologically defined by mean pulmonary arterial pressure of 25 mm Hg or greater at rest and is pathologically characterized by pulmonary vascular remodeling, including smooth muscle hypertrophy and intima thickening. Although significant progress has been made in the past decades in our understanding of PAH and in disease management, the prognosis is still poor, with a 1-year survival rate of 91.0% (2) and 3-year survival rate of 77% or less according to recent investigations (3-5). The principal treatments for PAH rely on approaches targeting the prostacyclin, endothelin, or NO pathways (phosphodiesterase inhibition) or, increasingly, on a combination of them (6-11). Few patients show indication for treatment with calcium channel...

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Section: Discussionsupporting

confidence: 93%

Section: Abstract: Sts; Trpc; Soce; Pulmonary Hypertensionmentioning

confidence: 99%

Section: Abstract: Sts; Trpc; Soce; Pulmonary Hypertensionmentioning

confidence: 99%

See 1 more Smart Citation

Sodium Tanshinone IIA Sulfonate Inhibits Canonical Transient Receptor Potential Expression in Pulmonary Arterial Smooth Muscle from Pulmonary Hypertensive Rats

Wang

Qian

Wan

et al. 2013

Am J Respir Cell Mol Biol

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“…Previous reports have demonstrated that Tanshinone IIA inhibited the proliferation of pulmonary artery smooth muscle cells (PASMCs) [3], lowered pulmonary artery pressure, and ameliorated the hypoxia-induced pulmonary artery remodeling [4]. These effects of Tanshinone IIA could delay the hypoxia-induced degradation of p27 via an Akt/Skp2-associated pathway [3].…”

Section: Introductionmentioning

confidence: 99%

Tanshinone IIA Promotes Pulmonary Artery Smooth Muscle Cell Apoptosisin Vitroby Inhibiting the JAK2/STAT3 Signaling Pathway

Chen

Liu

Wei

et al. 2014

Cell Physiol Biochem

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Background: Tanshinone IIA inhibits the proliferation of pulmonary artery smooth muscle cells (PASMCs), but the potential mechanisms of its effects on PASMCs apoptosis remain unclear. Methods: Rat were subjected to hypoxia for 9 days with or without Tanshinone IIA treatment. PASMCs were exposed to the conditions of 2% O₂ and 93% N₂ for 24 h in vitro. Hematoxylin and eosin (HE) staining was used to evaluate vascular remodeling. The Cell viability was determined using cell fluorescence staining and MTT assays, and apoptosis was assessed using flow cytometry. Protein expression was quantified by Western blotting. Results: Our results showed that Tanshinone IIA treatment reduced pulmonary artery media thickening in hypoxic rats. Tanshinone IIA reduced PASMC viability in a dose-dependent manner. Additionally, Tanshinone IIA promoted PASMC apoptosis, lowered Hsp60 levels, and upregulated caspase-3 expressions under hypoxic conditions. This pro-apoptotic effect of Tanshinone IIA might be due to the reduction of the phosphorylation of JAK2/STAT3 signaling markers and the increase in the levels of the downstream target, Cx43 in PASMCs. Conclusion: These data suggest that Tanshinone IIA promotes PASMC apoptosis during hypoxia and reverses vascular remodeling. This effect is mediated by modulating the expression of Hsp60, caspase-3, and Cx43 via the JAK2/STAT3 signaling pathway. These results might provide a new therapeutic target to explore a novel strategy for hypoxia-induced vessel remodeling.

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“…Clinical evidence and pharmacological research had proved STS to be effective for the treatment of various cardiovascular diseases, mainly through its antioxidant activity [1][2][3]. In addition, recent research suggested that STS posses a wide range of pharmacological activities, such as activating high conductance Ca 2+ activated K + channels, exhibiting a strong vasodilating effect against vasoconstriction, and playing protective effects on hypoxic pulmonary hypertension [4][5][6]. It was also reported that STS may be promising at treating some liver diseases [7].…”

Section: Introductionmentioning

confidence: 99%

Isolation and structure characterization of related impurities in Sodium Tanshinone IIA Sulfonate by LC/ESI-MSn and NMR

Wang

Yan

et al. 2012

Journal of Pharmaceutical and Biomedical Analysis

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Effects of sodium tanshinone II A sulphonate on hypoxic pulmonary hypertension in rats in vivo and on Kv2.1 expression in pulmonary artery smooth muscle cells in vitro

Cited by 27 publications

References 32 publications

Sodium Tanshinone IIA Sulfonate Inhibits Canonical Transient Receptor Potential Expression in Pulmonary Arterial Smooth Muscle from Pulmonary Hypertensive Rats

Sodium Tanshinone IIA Sulfonate Inhibits Canonical Transient Receptor Potential Expression in Pulmonary Arterial Smooth Muscle from Pulmonary Hypertensive Rats

Tanshinone IIA Promotes Pulmonary Artery Smooth Muscle Cell Apoptosisin Vitroby Inhibiting the JAK2/STAT3 Signaling Pathway

Isolation and structure characterization of related impurities in Sodium Tanshinone IIA Sulfonate by LC/ESI-MSn and NMR

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