Effect of Probucol on Antioxidant Properties of HDL in Patients with Heterozygous Familial Hypercholesterolemia

Miwako Inagaki, Yumiko Nakagawa-Toyama, Makoto Nishida, Kazuhiro Nakatani, Hajime Nakaoka, Miyako Kawase, Ryota Kawase, Kazumi Tsubakio-Yamamoto, Daisaku Masuda, Tohru Ohama, Akifumi Matsuyama, Masato Ishigami, Issei Komuro, Shizuya Yamashita

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Aim: High density lipoprotein (HDL) has multi-antiatherogenic effects such as antioxidation and anti-inflammation, in addition to being a key mediator of reverse cholesterol transport. Probucol, known as a lipid lowering drug, is also a potent antioxidant, but it decreases serum HDL cholesterol (HDL-C) levels. To elucidate the effect of probucol on antioxidant properties of HDL, we investigated the function of HDL derived from patients with heterozygous familial hypercholesterolemia (FH) who have been treated with probucol. Methods and Results: Probucol-treated FH patients (n=21) showed a 47% reduction of serum HDL-C levels compared to probucol-untreated FH patients (n=15). High performance liquid chro-matography (HPLC) analysis revealed that probucol diminished HDL particle size compared to the non-treated group. Antioxidant capacity of HDL was evaluated by its effect to protect reference LDL from oxidation induced in the presence of an oxidizing agent, AAPH. The HDL derived from the probucol-treated group demonstrated a significantly prolonged time to start oxidation by 112%, decreased the maximum oxidation rate by 14%, and lowered the maximum concentration of conjugated dienes formation by 15%. Furthermore, HDL-associated paraoxonase 1 (PON1) activity, but not platelet-activating factor acetyl-hydrolase (PAF-AH) correlated with these measurements of HDL anti-oxidative activity. Treatment with probucol in vitro and inhibition of PON1 activity demonstrated that probucol in HDL particles and increase of PON1 activity might largely contribute to the increase of HDL anti-oxidative activity. Conclusion: Probucol reduced HDL-C levels and HDL particle size in patients with heterozygous FH, while it concomitantly enhanced HDL anti-oxidative properties, possibly through increasing PON1 activity.

Original languageEnglish
Pages (from-to)643-656
Number of pages14
JournalJournal of atherosclerosis and thrombosis
Volume19
Issue number7
DOIs
Publication statusPublished - 07-08-2012

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Cardiology and Cardiovascular Medicine
  • Biochemistry, medical

Cite this

Inagaki, M., Nakagawa-Toyama, Y., Nishida, M., Nakatani, K., Nakaoka, H., Kawase, M., Kawase, R., Tsubakio-Yamamoto, K., Masuda, D., Ohama, T., Matsuyama, A., Ishigami, M., Komuro, I., & Yamashita, S. (2012). Effect of Probucol on Antioxidant Properties of HDL in Patients with Heterozygous Familial Hypercholesterolemia. Journal of atherosclerosis and thrombosis, 19(7), 643-656. https://doi.org/10.5551/jat.12807