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Ethyl pyruvate alleviates pulmonary arterial hypertension via PI3K-Akt signaling

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Abstract

Pulmonary arterial hypertension (PAH) is a pathophysiological syndrome that is extremely difficult to manage, and there is currently no effective treatment. We want to elucidate the therapeutic effect of ethyl pyruvate (EP) on PAH and its possible mechanism. Pulmonary artery endothelial cells (PAECs) were cultured in conventional low-oxygen environments, and cellular proliferation was monitored after treatment with EP. Expression of p-PI3K/Akt, LC3-II, and Beclin-1 was detected by Western blot. After hyperkinetic PAH rabbits’ models were treated with EP, hemodynamic data were collected. Right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Expression of p-PI3K/Akt, LC3-II, and Beclin-1 protein was also detected after using autophagy inhibitor and agonists. We found that EP could inhibit PAECs proliferation. After EP treatment, expression of p-PI3K/Akt was upregulated in vitro and in vivo. LC3-II and Beclin-1 were inhibited and their expression was lower after autophagy inhibitor was given, while after administration of autophagy agonists, their expression was higher than that in the EP alone group. Besides, EP attenuated PAH, and right ventricular hypertrophy and pulmonary vascular remodeling were also reversed. EP can reduce PAH and reverse vascular remodeling which is associated with inhibition of autophagy in PAECs based on PI3K-Akt signaling pathway. The results of this study can provide surgical opportunities for patients with severe PAH caused by congenital heart disease in clinical cardiovascular surgery.

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Data availability

The data that support the findings of this study are available from the corresponding author.

Abbreviations

PAH:

Pulmonary arterial hypertension

TUFM:

Tu translation elongation factor

EP:

Ethyl pyruvate

Atg:

Autophagy-related genes

ILAR:

Institute of Laboratory Animal Research

SPAP:

Systolic pulmonary arterial pressure

RV:

Right ventricle

LV + S:

Left ventricle plus septum

WT:

Wall thickness

WA:

Wall area

SD:

Standard deviation

MPAP:

Mean pulmonary arterial pressure

PAECs:

Pulmonary artery endothelial cells

TIGAR:

TP53-induced glycolysis and apoptosis regulator

ROS:

Reactive oxygen species

ALI:

Acute lung injury

I/R:

Ischemia/reperfusion

HMGB1/RAGE:

High mobility group protein B1/receptor for advanced glycation end-products

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Funding

This work was supported by the Shandong Provincial Natural Science Foundation of China (no. ZR2019PH024).

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Author notes

  1. Chuanzhen Liu, Kai Liu, Xin Lv and Jianhua Li have been contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, No. 107, West Wenhua Road, Jinan, 250012, Shandong, China

    Xin Lv, Jianhua Li, Ruyuan Wei, Lingwei Meng, Xiangjin Kong, Kaiming Wei, Mengmeng Tang, Kai Liu & Chuanzhen Liu

  2. Shandong University, No. 27, South Shanda Road, Jinan, 250100, Shandong, China

    Chuanzhen Liu

  3. Pantheum Biotechnology Co, LtdShandong, 250012, Jinan, China

    Chuanzhen Liu

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  1. Xin Lv
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  2. Jianhua Li
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  4. Lingwei Meng
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Contributions

Xin Lv contributed to study design, vivo and vitro experiments, data analysis, and paper writing; Chuanzhen Liu and Kai Liu contributed to study design and paper review; Ruyuan Wei, Lingwei Meng, Xiangjin Kong, Kaiming Wei, Mengmeng Tang and Jianhua Li contributed to data acquisition, data analysis and experiments. Chuanzhen Liu and Jianhua Li contributed to manuscript revision and final review.

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Correspondence to Kai Liu or Chuanzhen Liu.

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Experiments were carried out at Shandong University, Jinan, China with prior approval from the Institutional Review Board. (KYLL-2021(KS)-652).

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Lv, X., Li, J., Wei, R. et al. Ethyl pyruvate alleviates pulmonary arterial hypertension via PI3K-Akt signaling. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-05020-1

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