Hypoxia promotes pulmonary vascular remodeling via HIF-1α to regulate mitochondrial dynamics

Xi Chen; Jia-Mei Yao; Xia Fang; Cui Zhang; Yu-Shu Yang; Cheng-Ping Hu; Qiong Chen; Guang-Wei Zhong

doi:10.11909/j.issn.1671-5411.2019.12.003

Hypoxia promotes pulmonary vascular remodeling via HIF-1α to regulate mitochondrial dynamics

J Geriatr Cardiol. 2019 Dec;16(12):855-871. doi: 10.11909/j.issn.1671-5411.2019.12.003.

Authors

Xi Chen^{1

2}, Jia-Mei Yao^{1

3

4}, Xia Fang^{2

3}, Cui Zhang^{1

3}, Yu-Shu Yang^{1

3}, Cheng-Ping Hu^{1

2}, Qiong Chen^{1

3

4}, Guang-Wei Zhong^{1

3

4}

Affiliations

¹ National Center for Clinical Medicine for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, China.
² Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
³ Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China.
⁴ International Medical Center, Xiangya Hospital, Central South University, Changsha, China.

PMID: 31911790
PMCID: PMC6938735
DOI: 10.11909/j.issn.1671-5411.2019.12.003

Abstract

Background: Increasing research suggests that mitochondrial defect plays a major role in pulmonary hypertension (PH) pathogenesis. Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation and apoptosis balance. However, the molecular mechanism underlying of this balance is still unknown.

Methods: To clarify the biological effects of hypoxic air exposure and hypoxia-inducible factor-1α (HIF-1α) on pulmonary arterial smooth muscle cell (PASMC) and pulmonary arterial hypertension rats, the cells were cultured in a hypoxic chamber under oxygen concentrations. Cell viability, reactive oxygen species level, cell death, mitochondrial morphology, mitochondrial membrane potential, mitochondrial function and mitochondrial biosynthesis, as well as fission-and fusion-related proteins, were measured under hypoxic conditions. In addition, rats were maintained under hypoxic conditions, and the right ventricular systolic pressure, right ventricular hypertrophy index and right ventricular weight/body weight ratio were examined and recorded. Further, we assessed the role of HIF-1α in the development and progression of PH using HIF-1α gene knockdown using small interfering RNA transfection. Mdivi-1 treatment was performed before hypoxia to inhibit dynamin-related protein 1 (Drp1).

Results: We found that HIF-1α expression was increased during hypoxia, which was crucial for hypoxia-induced mitochondrial dysfunction and hypoxia-stimulated PASMCs proliferation and apoptosis. We also found that targeting mitochondrial fission Drp1 by mitochondrial division inhibitor Mdivi-1 was effective in PH model rats. The results showed that mitochondrial dynamics were involved in the pulmonary vascular remodeling under hypoxia in vivo and in vitro. Furthermore, HIF-1α also modulated mitochondrial dynamics in pulmonary vascular remodeling under hypoxia through directly regulating the expression of Drp1.

Conclusions: In conclusion, our data suggests that abnormal mitochondrial dynamics could be a marker for the early diagnosis of PH and monitoring disease progression. Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in PH.

Keywords: Dynamin-related protein 1; Hypoxia; Hypoxia-inducible factor-1α; Mitochondrial dynamics; Pulmonary vascular remodeling.

Institute of Geriatric Cardiology.