2. Academic Validation
  3. Therapeutic potential and protective role of GRK6 overexpression in pulmonary arterial hypertension

Therapeutic potential and protective role of GRK6 overexpression in pulmonary arterial hypertension

  • Vascul Pharmacol. 2023 Sep 22:153:107233. doi: 10.1016/j.vph.2023.107233.
Chenchen Liu 1,  Naifu Wan 1,  Lijiang Wei 1,  Wuwei Rong 1,  Wentong Zhu 1,  Meifeng Xie 2,  Yanling Zhang 2,  Zhihua Liu 2,  Qing Jing 3,  Ankang Lyu 4
Affiliations

Affiliations

  • 1 Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijiner Rd, Shanghai 200025, China.
  • 2 CAS Key Laboratory of Tissue Microenvironment and Tumour, Shanghai Institute of Nutrition and Health, Innovation Centre for Intervention of Chronic Disease and Promotion of Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China.
  • 3 CAS Key Laboratory of Tissue Microenvironment and Tumour, Shanghai Institute of Nutrition and Health, Innovation Centre for Intervention of Chronic Disease and Promotion of Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China. Electronic address: [email protected].
  • 4 Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijiner Rd, Shanghai 200025, China. Electronic address: [email protected].
PMID: 37742818 DOI: 10.1016/j.vph.2023.107233
Abstract

Abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs) is a key mechanism in the development of pulmonary arterial hypertension (PAH). Signal transducer and activator of transcription 3 (STAT3) signalling plays a critical role in modulating PASMC proliferation, and G-protein-coupled receptor kinase 6 (GRK6) regulates the STAT3 pathway. However, the mechanism underlying the relationship between GRK6 and PAH remains unclear. In this study, we aimed to investigate the role of GRK6 in PAH and determine its potential as a therapeutic target. We utilised hypoxia- and SU5416-induced PAH mouse models and a monocrotaline-induced PAH rat model to analyse the involvement of GRK6. We conducted gain- and loss-of-function experiments using mouse PASMCs. Modulation of GRK6 expression was achieved via a lentiviral vector in vitro and an adeno-associated virus serotype 1 encoding GRK6 in vivo. GRK6 was significantly downregulated in the lung tissues of PAH mice and rats, predominantly in PASMCs. Knockout of GRK6 exacerbated PAH, while both therapeutic and prophylactic overexpression of GRK6 alleviated PAH, as evidenced by a reduction in right ventricular systolic pressure, right ventricular wall to left ventricular wall plus ventricular septum ratio, pulmonary vascular media thickness, and pulmonary vascular muscularisation. Mechanistically, GRK6 overexpression attenuated hypoxia-induced PASMC proliferation and STAT3 phosphorylation. Conversely, knockdown of GRK6 promoted hypoxia-induced proliferation, which was mitigated by a STAT3 Inhibitor. Our findings highlight the potential protective and beneficial roles of GRK6 in PAH; we propose a lung-targeted GRK6 gene therapy utilizing adeno-associated virus serotype 1 as a potential treatment approach for patients with PAH.

Keywords

G-protein-coupled receptor kinase 6; Pulmonary arterial hypertension; Signal transducer and activator of transcription 3; Smooth muscle cell; Vessel remodelling.

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