ALDH2 (Aldehyde Dehydrogenase 2) Protects Against Hypoxia-Induced Pulmonary Hypertension

Yu Zhao; Bailu Wang; Jian Zhang; Dayu He; Qun Zhang; Chang Pan; Qiuhuan Yuan; Yinan Shi; Haiyang Tang; Feng Xu; Shujian Wei; Yuguo Chen

doi:10.1161/ATVBAHA.119.312946

ALDH2 (Aldehyde Dehydrogenase 2) Protects Against Hypoxia-Induced Pulmonary Hypertension

Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2303-2319. doi: 10.1161/ATVBAHA.119.312946. Epub 2019 Sep 12.

Authors

Yu Zhao^{1

2

3

4}, Bailu Wang⁵, Jian Zhang^{1

2

3

4}, Dayu He^{1

2

3

4}, Qun Zhang^{1

2

3

4}, Chang Pan^{1

2

3

4}, Qiuhuan Yuan^{1

2

3

4}, Yinan Shi⁶, Haiyang Tang^{6

7}, Feng Xu^{1

2

3

4}, Shujian Wei^{1

2

3

4}, Yuguo Chen^{1

2

3

4}

Affiliations

¹ From the Department of Emergency and Chest Pain Center, Qilu Hospital, Shandong University (Y.Z., J.Z., D.H., Q.Z., C.P., Q.Y., F.X., S.W., Y.C.), Qilu Hospital of Shandong University, Jinan.
² Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Shandong University (Y.Z., J.Z., D.H., Q.Z., C.P., Q.Y., F.X., S.W., Y.C.), Qilu Hospital of Shandong University, Jinan.
³ Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Shandong University (Y.Z., J.Z., D.H., Q.Z., C.P., Q.Y., F.X., S.W., Y.C.), Qilu Hospital of Shandong University, Jinan.
⁴ The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences; The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Shandong University (Y.Z., J.Z., D.H., Q.Z., C.P., Q.Y., F.X., S.W., Y.C.), Qilu Hospital of Shandong University, Jinan.
⁵ Clinical Trial Center (B.W.), Qilu Hospital of Shandong University, Jinan.
⁶ College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China (Y.S., H.T.).
⁷ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangdong, China (H.T.).

PMID: 31510791
DOI: 10.1161/ATVBAHA.119.312946

Abstract

Objective: Hypoxia-induced pulmonary hypertension (HPH) increases lipid peroxidation with generation of toxic aldehydes that are metabolized by detoxifying enzymes, including ALDH2 (aldehyde dehydrogenase 2). However, the role of lipid peroxidation and ALDH2 in HPH pathogenesis remain undefined. Approach and Results: To determine the role of lipid peroxidation and ALDH2 in HPH, C57BL/6 mice, ALDH2 transgenic mice, and ALDH2 knockout (ALDH2^-/-) mice were exposed to chronic hypoxia, and recombinant tissue-specific ALDH2 overexpression adeno-associated viruses were introduced into pulmonary arteries via tail vein injection for ALDH2 overexpression. Human pulmonary artery smooth muscle cells were used to elucidate underlying mechanisms in vitro. Chronic hypoxia promoted lipid peroxidation due to the excessive production of reactive oxygen species and increased expression of lipoxygenases in lung tissues. 4-hydroxynonenal but not malondialdehyde level was increased in hypoxic lung tissues which might reflect differences in detoxifying enzymes. ALDH2 overexpression attenuated the development of HPH, whereas ALDH2 knockout aggravated it. Specific overexpression of ALDH2 using AAV1 (adeno-associated virus)-ICAM (intercellular adhesion molecule) 2p-ALDH2 and AAV2-SM22αp (smooth muscle 22 alpha)-ALDH2 viral vectors in pulmonary artery smooth muscle cells, but not endothelial cells, prevented the development of HPH. Hypoxia or 4-hydroxynonenal increased stabilization of HIF (hypoxia-inducible factor)-1α, phosphorylation of Drp1 (dynamin-related protein 1) at serine 616, mitochondrial fission, and pulmonary artery smooth muscle cells proliferation, whereas ALDH2 activation suppressed the latter 3.

Conclusions: Increased 4-hydroxynonenal level plays a critical role in the development of HPH. ALDH2 attenuates the development of HPH by regulating mitochondrial fission and smooth muscle cell proliferation suggesting ALDH2 as a potential new therapeutic target for pulmonary hypertension.

Keywords: hypoxia; lipid peroxidation; mitochondrial fission; pulmonary artery; pulmonary hypertension.

Publication types

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

MeSH terms

Aldehyde Dehydrogenase, Mitochondrial / genetics
Aldehyde Dehydrogenase, Mitochondrial / metabolism*
Aldehydes / metabolism
Animals
Cell Proliferation
Cells, Cultured
Down-Regulation
Humans
Hypertension, Pulmonary / enzymology*
Hypertension, Pulmonary / metabolism
Hypoxia
Lipid Peroxidation
Lipoxygenases / metabolism
Lung / enzymology
Male
Malondialdehyde / metabolism
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Mitochondrial Dynamics
Muscle, Smooth, Vascular / cytology
Myocytes, Smooth Muscle / metabolism
Pulmonary Artery
Reactive Oxygen Species
Up-Regulation

Substances

Aldehydes
Reactive Oxygen Species
Malondialdehyde
Lipoxygenases
ALDH2 protein, mouse
Aldehyde Dehydrogenase, Mitochondrial
4-hydroxy-2-nonenal