AD-9308 ameliorates the impacts of 4-HNE on the progress of pulmonary arterial hypertension in aldehyde dehydrogenase 2*1*2 knock-in mice

ALDH2 醛脱氢酶 医学 伊诺斯 药理学 内科学 内分泌学 生物化学 一氧化氮 化学 一氧化氮合酶
作者
Yen-Hung Chou,Y N Lee,Cheng‐Huang Su,Horng‐Jen Yeh,Yu‐Hung Wu
出处
期刊:European Heart Journal [Oxford University Press]
卷期号:43 (Supplement_2)
标识
DOI:10.1093/eurheartj/ehac544.3062
摘要

Abstract Endothelial dysfunctions play a critical role on the development of pulmonary arterial hypertension (PAH). It has been reported that the one-year mortality rate is still up to 15% even with PAH-targeted therapy, implying that there may be untargeted pathways. 4-hydroxynenonal (4-HNE), an unsaturated aldehyde, is highly induced in the lungs of PAH animals and its serum levels were also reported to be higher in PAH patients. 4-HNE is metabolized by mitochondrial aldehyde dehydrogenase (ALDH2), which is dysfunctional in near 40% of East Asian people. Currently, the impacts of 4-HNE on endothelial dysfunctions in the development of PAH are unclear. In terms of translational medicine, we proposed that modulation of 4-HNE level may alleviate the progress of PAH patients with ALDH2 deficiency. We found that 4-HNE alone was not sufficient to induce pulmonary artery endothelial cell (PAEC) functional changes, including proliferation, migration and tube formation, whereas their effects emerge from the depletion of ALDH2. We further mimicked human ALDH2 functional deficiency by using daidzin (DZN), an inhibitor which is able to block the substrate binding site of ALDH2. ALDH2 functional inhibition alone did not induce any PAEC functional change, while an add-on of 4-HNE impaired PAEC functions. In addition, 4-HNE significantly reduced eNOS activity with combined DZN treatment. Consistent with the mechanism of ALDH2 activity-mediated angiogensis, ALDH2 enhancers Alda-1 and AD-5591 completely reverse the anti-angiogenic effects of 4-HNE in the presence of DZN. To further confirm whether ALDH2 functional deficiency impact on PAH development in mammals, heterozygous ALDH2*1/*2 transgenic and wild-type mice were subjected to chronic hypoxia to induce PAH. ALDH2*1/*2 transgenic mice had similar right ventricular systolic pressure (RVSP) as wild-type mice. However, after exposure to chronic hypoxia, ALDH2*1/*2 transgenic mice indeed developed a significantly higher RVSP than that in wild-type mice. Furthermore, we demonstrated that 4-HNE expression was profoundly enhanced in ALDH2*1/*2 transgenic mice by chronic hypoxia-induced PAH with pulmonary artery smooth muscle cell hyperplasia. More importantly, we found that AD-9308, an enhancer of ALDH2 significantly decreased hypoxia-induced RVSP elevation in heterozygous ALDH2*1/*2 transgenic mice. Taken together, our data demonstrate that 4-HNE and ALDH2 functional deficiency potentially contribute to PAH development and worsening, and that ALDH2 enhancers may be promising as a PAH adjunct therapy, particularly for patients with ALDH2 nonfunctional alleles. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Science and Technology, Taiwan

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