Targeting the RhoA-ROCK pathway to regulate T-cell homeostasis in hypoxia-induced pulmonary arterial hypertension

Cheng Li; Ping-Ping Liu; Dou-Dou Tang; Rong Song; Yi-Qing Zhang; Si Lei; Shang-Jie Wu

doi:10.1016/j.pupt.2018.04.004

Targeting the RhoA-ROCK pathway to regulate T-cell homeostasis in hypoxia-induced pulmonary arterial hypertension

Pulm Pharmacol Ther. 2018 Jun:50:111-122. doi: 10.1016/j.pupt.2018.04.004. Epub 2018 Apr 17.

Authors

Cheng Li¹, Ping-Ping Liu², Dou-Dou Tang¹, Rong Song¹, Yi-Qing Zhang¹, Si Lei¹, Shang-Jie Wu³

Affiliations

¹ Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China; Research Unit of Respiratory Disease, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China.
² Department of Emergency, Hunan Children's Hospital, Changsha, Hunan 410007, PR China.
³ Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China; Research Unit of Respiratory Disease, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China. Electronic address: wushangjie@csu.edu.cn.

PMID: 29673911
DOI: 10.1016/j.pupt.2018.04.004

Abstract

Background: Hypoxic pulmonary arterial hypertension (PAH) is a crippling disease with limited therapeutic methods. The imbalance of T helper 17 cell (Th17)/regulatory T cell (Treg) plays an important role in the development of Hypoxic PAH. However, whether targeting the ras homolog family member A-Rho kinase (RhoA-ROCK) pathway (activation and inhibition) by lysophosphatidic acid (LPA) and fasudil (FSD) regulate T-cell homeostasis in Hypoxic PAH remain unknown.

Objective: To examine the effects of LPA and FSD on hypoxic pulmonary vascular remodeling and homeostasis of Th17/Treg cells in Hypoxic PAH.

Methods: Rats were exposed to hypoxia (10 ± 0.5% O₂) to induce Hypoxic PAH. The experiments consists of two parts. Forty rats were randomly divided into four groups (n = 10): normoxia group, normoxia + LPA group, hypoxia group and hypoxia + LPA group. Thirty rats were randomly divided into another three groups (n = 10): normoxia group, hypoxia group, and hypoxia + FSD group. Rats in normoxia + LPA group and hypoxia + LPA group were intraperitoneally injected 40 μg/kg LPA daily. Rats in hypoxia + FSD group were intraperitoneally injected 30 mg/kg fasudil daily. The effects of LPA and FSD on the development of hypoxic PAH and right ventricle (RV) hypertrophy, on pulmonary vascular remodeling, and on changes of Th17/Treg cells and levels of interleukin-17 (IL-17) and IL-10 were examined.

Results: PAH and RV hypertrophy occurred in rats exposed to hypoxia. LPA exacerbated hypoxic pulmonary vascular remodeling and FSD inhibited it. LPA increased Th17/Treg imbalance in peripheral blood and spleen. However, after treatment with FSD, hypoxic PAH rats showed an obvious reduction of Th17 cells as well as an increase of Treg cells. LPA increased the expression of phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) and reduced the p-STAT5 in peripheral blood and spleen in hypoxic PAH rats. The expression of p-STAT3 and p-STAT5 in hypoxic PAH rats treated with FSD showed opposite changes. LPA increased the expression of IL-17 and reduced the IL-10 in small intrapulmonary arteries and serum in hypoxic PAH. However, the expression of IL-17 and IL-10 in hypoxic PAH rats treated with FSD showed opposite changes.

Conclusions: Activation and inhibition of RhoA-ROCK pathway by LPA and FSD modulated the homeostasis of Th17/Treg cells via regulating STAT3/STAT5 phosphorylation in hypoxic PAH. Thus, Apart from influence of pulmonary vascular remodeling, regulation of Th17/Treg homeostasis by RhoA-ROCK pathway play a key role in hypoxic PAH.

Keywords: Fasudil; Hypoxic pulmonary arterial hypertension; Lysophosphatidic acid; Regulatory T cell; T helper 17 cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
Animals
Hypertension, Pulmonary / drug therapy*
Hypertension, Pulmonary / metabolism
Hypertension, Pulmonary / pathology*
Hypoxia / metabolism
Hypoxia / pathology*
Interleukin-10 / metabolism
Interleukin-17 / metabolism
Lysophospholipids / pharmacology*
Male
Pulmonary Artery / drug effects
Pulmonary Artery / pathology
Random Allocation
Rats
Signal Transduction / drug effects
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / metabolism
T-Lymphocytes, Regulatory / pathology*
Th17 Cells / drug effects
Th17 Cells / metabolism
Th17 Cells / pathology*
Vascular Remodeling / drug effects
rho GTP-Binding Proteins / antagonists & inhibitors*
rho GTP-Binding Proteins / metabolism
rho-Associated Kinases / antagonists & inhibitors*

Substances

Interleukin-17
Lysophospholipids
Interleukin-10
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
rho-Associated Kinases
RhoA protein, rat
rho GTP-Binding Proteins
lysophosphatidic acid
fasudil