Maxacalcitol (22-Oxacalcitriol (OCT)) Retards Progression of Left Ventricular Hypertrophy with Renal Dysfunction Through
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ORIGINAL ARTICLE
Maxacalcitol (22-Oxacalcitriol (OCT)) Retards Progression of Left Ventricular Hypertrophy with Renal Dysfunction Through Inhibition of Calcineurin-NFAT Activity Kazunori Inoue 1 & Isao Matsui 1 & Takayuki Hamano 2,3 & Keiji Okuda 4 & Yasumasa Tsukamoto 5 & Ayumi Matsumoto 1 & Karin Shimada 1 & Seiichi Yasuda 1 & Yusuke Katsuma 1 & Yoshitsugu Takabatake 1 & Masaru Tanaka 6 & Noriko Tanaka 6 & Toshiaki Mano 7 & Tetsuo Minamino 8 & Yasushi Sakata 5 & Yoshitaka Isaka 1 Accepted: 10 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose Left ventricular hypertrophy (LVH) is a cardiovascular complication highly prevalent in patients with chronic kidney disease (CKD). Previous studies analyzing 1α-hydroxylase or vitamin D receptor (Vdr) knockout mice revealed active vitamin D as a promising agent inhibiting LVH progression. Paricalcitol, an active vitamin D analog, failed to suppress the progression of LV mass index (LVMI) in pre-dialysis patients with CKD. As target genes of activated VDR differ depending on its agonists, we examined the effects of maxacalcitol (22-oxacalcitriol: OCT), a less calcemic active vitamin D analog, on LVH in hemodialysis patients and animal LVH models with renal insufficiency. Methods In retrospective cohort study, patients treated with OCT who underwent hemodialysis were enrolled. Using cardiac echocardiography, LV mass was evaluated by the area-length method. In animal study, angiotensin II (Ang II)-infused Wister rats with heminephrectomy or Ang II-stimulated neonatal rat ventricular myocytes (NRVM) were treated with OCT. Results OCT significantly inhibited the progression of LVMI in hemodialysis patients. In Ang II-infused heminephrectomized rats, OCT suppressed the progression of LVH in a blood pressure-independent manner. OCT also suppressed the activity of calcineurin in the left ventricle of model rats. Specifically, OCT reduced the protein levels of calcineurin A, but not the mRNA levels of Ppp3ca (calcineurin Aα). Luciferase assays showed that OCT increased the promoter activity of Fbxo32 (atrogin1), an E3 ubiquitin ligase targeting calcineurin A. Finally, OCT promoted ubiquitination and degradation of calcineurin A. Conclusion Our works indicated that OCT retards progression of LVH through calcineurin-NFAT pathway, which reveal a novel aspect of OCT in attenuating pathological LVH. Keywords Left ventricular hypertrophy . Chronic kidney disease . Active vitamin D analog . Angiotensin II . Calcineurin A . Atrogin1
* Isao Matsui [email protected] 1
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Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan Department of Inter-Organ Communication Research in Kidney Disease, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan Department of Nephrology, Nagoya City University Graduate School of Medical Science and Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan
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Cardiovascular
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