PMID- 33206298
OWN - NLM
STAT- MEDLINE
DCOM- 20211213
LR  - 20211214
IS  - 1573-7241 (Electronic)
IS  - 0920-3206 (Linking)
VI  - 35
IP  - 2
DP  - 2021 Apr
TI  - Maxacalcitol (22-Oxacalcitriol (OCT)) Retards Progression of Left Ventricular 
      Hypertrophy with Renal Dysfunction Through Inhibition of Calcineurin-NFAT 
      Activity.
PG  - 381-397
LID - 10.1007/s10557-020-07111-9 [doi]
AB  - PURPOSE: Left ventricular hypertrophy (LVH) is a cardiovascular complication 
      highly prevalent in patients with chronic kidney disease (CKD). Previous studies 
      analyzing 1alpha-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 Aalpha). 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.
FAU - Inoue, Kazunori
AU  - Inoue K
AD  - Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 
      Yamada-oka, Suita, Osaka, 565-0871, Japan.
FAU - Matsui, Isao
AU  - Matsui I
AD  - Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 
      Yamada-oka, Suita, Osaka, 565-0871, Japan. matsui@kid.med.osaka-u.ac.jp.
FAU - Hamano, Takayuki
AU  - Hamano T
AD  - Department of Inter-Organ Communication Research in Kidney Disease, Osaka 
      University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, 
      Japan.
AD  - 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.
FAU - Okuda, Keiji
AU  - Okuda K
AD  - Cardiovascular Division, Osaka Saiseikai Senri Hospital, Suita, Osaka, 565-0862, 
      Japan.
FAU - Tsukamoto, Yasumasa
AU  - Tsukamoto Y
AD  - Department of Cardiovascular Medicine, Osaka University Graduate School of 
      Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
FAU - Matsumoto, Ayumi
AU  - Matsumoto A
AD  - Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 
      Yamada-oka, Suita, Osaka, 565-0871, Japan.
FAU - Shimada, Karin
AU  - Shimada K
AD  - Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 
      Yamada-oka, Suita, Osaka, 565-0871, Japan.
FAU - Yasuda, Seiichi
AU  - Yasuda S
AD  - Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 
      Yamada-oka, Suita, Osaka, 565-0871, Japan.
FAU - Katsuma, Yusuke
AU  - Katsuma Y
AD  - Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 
      Yamada-oka, Suita, Osaka, 565-0871, Japan.
FAU - Takabatake, Yoshitsugu
AU  - Takabatake Y
AD  - Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 
      Yamada-oka, Suita, Osaka, 565-0871, Japan.
FAU - Tanaka, Masaru
AU  - Tanaka M
AD  - Department of Nephrology, Tanaka Kitanoda Hospital, 707 Kitanoda, Sakai-ku, 
      Sakai, Osaka, 599-8123, Japan.
FAU - Tanaka, Noriko
AU  - Tanaka N
AD  - Department of Nephrology, Tanaka Kitanoda Hospital, 707 Kitanoda, Sakai-ku, 
      Sakai, Osaka, 599-8123, Japan.
FAU - Mano, Toshiaki
AU  - Mano T
AD  - Department of Cardiology, Kansai Rosai Hospital, 3-1-69 Inabasou, Amagasaki, 
      Hyogo, 660-8511, Japan.
FAU - Minamino, Tetsuo
AU  - Minamino T
AD  - Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University 
      Graduate School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 
      761-0793, Japan.
FAU - Sakata, Yasushi
AU  - Sakata Y
AD  - Department of Cardiovascular Medicine, Osaka University Graduate School of 
      Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
FAU - Isaka, Yoshitaka
AU  - Isaka Y
AD  - Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 
      Yamada-oka, Suita, Osaka, 565-0871, Japan.
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
DEP - 20201118
PL  - United States
TA  - Cardiovasc Drugs Ther
JT  - Cardiovascular drugs and therapy
JID - 8712220
RN  - 0 (NFATC Transcription Factors)
RN  - EC 3.1.3.16 (Calcineurin)
RN  - FXC9231JVH (Calcitriol)
RN  - N2UJM5NBF6 (maxacalcitol)
SB  - IM
MH  - Aged
MH  - Animals
MH  - Calcineurin/drug effects
MH  - Calcitriol/*analogs & derivatives/pharmacology
MH  - Cell Culture Techniques
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Hypertrophy, Left Ventricular/*drug therapy/*etiology/*pathology
MH  - Male
MH  - Middle Aged
MH  - Myocytes, Cardiac/drug effects
MH  - NFATC Transcription Factors/metabolism
MH  - Pregnancy
MH  - Rats
MH  - Rats, Wistar
MH  - Renal Insufficiency/*complications
MH  - Retrospective Studies
OTO - NOTNLM
OT  - Active vitamin D analog
OT  - Angiotensin II
OT  - Atrogin1
OT  - Calcineurin A
OT  - Chronic kidney disease
OT  - Left ventricular hypertrophy
EDAT- 2020/11/19 06:00
MHDA- 2021/12/15 06:00
CRDT- 2020/11/18 12:13
PHST- 2020/11/10 00:00 [accepted]
PHST- 2020/11/19 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2020/11/18 12:13 [entrez]
AID - 10.1007/s10557-020-07111-9 [pii]
AID - 10.1007/s10557-020-07111-9 [doi]
PST - ppublish
SO  - Cardiovasc Drugs Ther. 2021 Apr;35(2):381-397. doi: 10.1007/s10557-020-07111-9. 
      Epub 2020 Nov 18.