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Oxidative stress-responsive apoptosis-inducing protein in patients with heterozygous familial hypercholesterolemia

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Abstract

Oxidative stress, an inducer of apoptosis, plays a critical role in ischemia/reperfusion injury and atherosclerosis. We previously identified an apoptosis-inducing ligand, the post-translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A), ‘oxidative stress-responsive apoptosis-inducing protein’ (ORAIP). In this study, we investigated the role of ORAIP in patients with heterozygous familial hypercholesterolemia (HeFH), a leading cause of premature cardiovascular disease. We analyzed plasma ORAIP and oxidized low-density lipoprotein (oxLDL) levels in 60 patients with HeFH (60% male, 57.0 ± 13.6 years of age) and 20 patients with LDL-C hypercholesterolemia (DL, 85% male, 64.1 ± 13.3 years of age). The coronary artery atherosclerosis from the patients with HeFH who had a coronary artery bypass graft was investigated by double immunostaining. The plasma ORAIP levels in the patients with HeFH were significantly elevated compared to those in the patients with DL (73.5 ± 46.0 vs. 48.3 ± 21.4 ng/mL, p = 0.0277). The plasma oxLDL levels in HeFH patients were also elevated (156.8 ± 65.2 vs. 123.7 ± 46.6 mg/dL, p = 0.0461) compared to those in DL patients and correlated with maxLDL-C levels (R = 0.4454, p = 0.00648). Double-immunostaining of ORAIP and oxLDL in the coronary artery from patients with HeFH who had a coronary artery bypass graft showed that ORAIP and oxLDL were colocalized with apoptotic vascular smooth muscle cells in the atherosclerotic plaque. ORAIP plays a role in the development of oxidative stress-induced atherosclerosis and may be an important therapeutic target for plaque rupture in patients with HeFH.

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Acknowledgements

K.S. was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a research support grant from Initiative for Realizing Diversity in the Research Environment.

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Authors and Affiliations

  1. Department of Cardiology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Kayoko Sato & Nobuhisa Hagiwara

  2. Division of Cardiovascular Medicine, The Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan

    Takako Yao

  3. Laboratory of Bioanalytical Chemistry, Tohoku Medical and Pharmaceutical University, Sendai, Japan

    Tsutomu Fujimura

  4. Division of Proteomics and Biomolecular Science, Graduate School of Medicine, BioMedical Research Center, Juntendo University, Tokyo, Japan

    Kimie Murayama

  5. Department of Biofunctional Microbiota, School of Medicine, Juntendo University, Tokyo, Japan

    Ko Okumura & Yoshinori Seko

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  1. Kayoko Sato
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Correspondence to Kayoko Sato.

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Sato, K., Yao, T., Fujimura, T. et al. Oxidative stress-responsive apoptosis-inducing protein in patients with heterozygous familial hypercholesterolemia. Heart Vessels 36, 1923–1932 (2021). https://doi.org/10.1007/s00380-021-01898-9

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