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. 2022 May 20;42(5):718-723.
doi: 10.12122/j.issn.1673-4254.2022.05.13.

[Tanshinone IIA alleviates monocrotaline-induced pulmonary hypertension in rats through the PI3K/Akt-eNOS signaling pathway]

[Article in Chinese]
X Zhang  1   2   3   4 , S Liu  1   2 , Y Sun  5 , G Li  1   2   3
Affiliations

[Tanshinone IIA alleviates monocrotaline-induced pulmonary hypertension in rats through the PI3K/Akt-eNOS signaling pathway]

[Article in Chinese]
X Zhang et al. Nan Fang Yi Ke Da Xue Xue Bao. .

Abstract
in English, Chinese

Objective: To explore the therapeutic mechanism of tanshinone IIA in the treatment of pulmonary arterial hypertension (PAH) in rats.

Methods: A total of 100 male SD rats were randomized into 5 groups (n=20), and except for those in the control group with saline injection, all the rats were injected with monocrotaline (MCT) on the back of the neck to establish models of pulmonary hypertension. Two weeks after the injection, the rat models received intraperitoneal injections of tanshinone IIA (10 mg/kg), phosphatidylinositol 3 kinase (PI3K) inhibitor (1 mg/kg), both tanshinone IIA and PI3K inhibitor, or saline (model group) on a daily basis. After 2 weeks of treatment, HE staining and α-SMA immunofluorescence staining were used to evaluate the morphology of the pulmonary vessels of the rats. The phosphorylation levels of PI3K, protein kinase B (PKB/Akt) and endothelial nitric oxide synthase (eNOS) in the lung tissue were determined with Western blotting; the levels of eNOS and NO were measured using enzyme-linked immunosorbent assay (ELISA).

Results: The results of HE staining and α-SMA immunofluorescence staining showed that tanshinone IIA effectively inhibited MCT-induced pulmonary artery intimamedia thickening and muscularization of the pulmonary arterioles (P < 0.01). The results of Western blotting showed that treatment with tanshinone IIA significantly increased the phosphorylation levels of PI3K, Akt and eNOS proteins in the lung tissue of PAH rats; ELISA results showed that the levels of eNOS and NO were significantly decreased in the rat models after tanshinone IIA treatment (P < 0.01).

Conclusion: Treatment with tanshinone IIA can improve MCT-induced pulmonary hypertension in rats through the PI3K/Akt-eNOS signaling pathway.

目的: 探究丹参酮IIA治疗野百合碱所致大鼠肺动脉高压（PAH）的作用机制。

方法: 选取100只SD雄性大鼠，按随机数字表法分为5组（20只/组）：模型组（MCT）、丹参酮IIA组（TIIA）、丹参酮IIA+PI3K抑制剂组（TP）、PI3K抑制剂组（PI）、对照组。除对照组颈背部注射等体积生理盐水外，剩余大鼠均颈背部注射野百合碱（MCT）诱导肺动脉高压模型。2周后，丹参酮IIA组腹腔注射丹参酮IIA10 mg/kg进行治疗，丹参酮IIA+PI3K抑制剂组注射丹参酮IIA10 mg/kg+PI3K抑制剂1 mg/kg，PI3K抑制剂组注射PI3K抑制剂1 mg/kg，对照组和模型组均腹腔注射等体积生理盐水。治疗2周后，采用苏木精-伊红（HE）染色实验和α-SMA免疫荧光染色实验评估大鼠肺血管形态；Western blot实验评估大鼠肺组织中磷脂酰肌醇3激酶（PI3K）、蛋白激酶B（PKB/ Akt）、内皮型一氧化氮合酶（eNOS）的磷酸化水平；ELISA法测定eNOS、NO水平。

结果: HE染色实验和α-SMA免疫荧光染色证实丹参酮IIA能有效抑制PAH大鼠肺血管中膜厚度和血管肌化水平（P < 0.01）；Western blot实验结果显示丹参酮IIA能够显著提高PAH大鼠肺组织中PI3K、Akt和eNOS蛋白的磷酸化水平；ELISA实验结果显示模型组eNOS、NO水平降低（P < 0.01）。

结论: 丹参酮IIA能够通过介导PI3K/Akt-eNOS信号通路改善野百合碱所致大鼠肺动脉高压。

Keywords: PI3K/Akt-eNOS; monocrotaline; pulmonary hypertension; signaling pathway; tanshinone IIA.

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Figures

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丹参酮IIA对MCT诱导大鼠右心室收缩压和右心室肥厚指数的影响 Effect of tanshinone IIA on right ventricular systolic blood pressure (RVSP, A) and right ventricular hypertrophy index (RVHI, B) in MCT-treated rats. ***P < 0.001 vs MCT group.
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丹参酮IIA对MCT诱导大鼠肺动脉中膜厚度影响 Effect of tanshinone IIA on MCT-induced pulmonary artery intima-media thickening in rats. A: HE staining (Original magnification: ×200). B: Wall thickness. **P < 0.01 vs MCT group; ***P < 0.001 vs MCT group.
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丹参酮IIA对MCT诱导大鼠肺小动脉肌化影响 Effect of tanshinone IIA on MCT-induced pulmonary arteriole muscularization in rats. A: α-SMA immunofluorescent staining (×200). B: Proportion of fully muscularized pulmonary small vessels. ***P < 0.01 vs MCT group.
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PI3K/Akt-eNOS信号通路蛋白表达情况 The protein expression of PI3K/Akt-eNOS signaling pathway. A: The expressions of P-PI3K, PI3K, P-AKT, AKT, P-eNOS, eNOS, GAPDH were analyzed by western blot. (B-D): The phosphorylated protein bands were standardized to total protein expression bands. ***P < 0.001 vs MCT group.
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丹参酮IIA降低MCT诱导大鼠血清中eNOS、NO含量 Tanshinone IIA reduces serum levels of eNOS (A) and NO (B) in MCT-treated rats. ***P < 0.001 vs MCT group.
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