Theranostics 2021; 11(6):2505-2521. doi:10.7150/thno.46192

Research Paper

DRD1 downregulation contributes to mechanical stretch-induced lung endothelial barrier dysfunction

Yan Wang1*, Yu-Jian Liu2*, Dun-Feng Xu1*, Hui Zhang1*, Chu-Fan Xu1, Yan-Fei Mao1, Zhou Lv1, Xiao-Yan Zhu3✉, Lai Jiang1✉

1. Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.
2. School of Kinesiology, The key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, 200438, China.
3. Department of Physiology, Navy Medical University, Shanghai, 200433, China.
* These authors contributed equally to this work and should be considered as co-first authors.

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Citation:
Wang Y, Liu YJ, Xu DF, Zhang H, Xu CF, Mao YF, Lv Z, Zhu XY, Jiang L. DRD1 downregulation contributes to mechanical stretch-induced lung endothelial barrier dysfunction. Theranostics 2021; 11(6):2505-2521. doi:10.7150/thno.46192. Available from https://www.thno.org/v11p2505.htm

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Abstract

Rationale: The lung-protective effects of dopamine and its role in the pathology of ventilator-induced lung injury (VILI) are emerging. However, the underlying mechanisms are still largely unknown.

Objective: To investigate the contribution of dopamine receptor dysregulation in the pathogenesis of VILI and therapeutic potential of dopamine D1 receptor (DRD1) agonist in VILI.

Methods: The role of dopamine receptors in mechanical stretch-induced endothelial barrier dysfunction and lung injury was studied in DRD1 knockout mice, in isolated mouse lung vascular endothelial cells (MLVECs), and in lung samples from patients who underwent pulmonary lobectomy with mechanical ventilation for different time periods.

Measurements and Main Results: DRD1 was downregulated in both surgical patients and mice exposed to mechanical ventilation. Prophylactic administration of dopamine or DRD1 agonist attenuated mechanical stretch-induced lung endothelial barrier dysfunction and lung injury. By contrast, pulmonary knockdown or global knockout of DRD1 exacerbated these effects. Prophylactic administration of dopamine attenuated mechanical stretch-induced α-tubulin deacetylation and subsequent endothelial hyperpermeability through DRD1 signaling. We identified that cyclic stretch-induced glycogen-synthase-kinase-3β activation led to phosphorylation and activation of histone deacetylase 6 (HDAC6), which resulted in deacetylation of α-tubulin. Upon activation, DRD1 signaling attenuated mechanical stretch-induced α-tubulin deacetylation and subsequent lung endothelial barrier dysfunction through cAMP/exchange protein activated by cAMP (EPAC)-mediated inactivation of HDAC6.

Conclusions: This work identifies a novel protective role for DRD1 against mechanical stretch-induced lung endothelial barrier dysfunction and lung injury. Further study of the mechanisms involving DRD1 in the regulation of microtubule stability and interference with DRD1/cAMP/EPAC/HDAC6 signaling may provide insight into therapeutic approaches for VILI.

Keywords: DRD1, mechanical ventilation, cyclic stretch, microtubule, pulmonary vascular endothelial cell