Maxacalcitol (22-Oxacalcitriol (OCT)) Retards Progression of Left Ventricular Hypertrophy with Renal Dysfunction Through Inhibition of Calcineurin-NFAT Activity.
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.
['Inoue|Kazunori|K|', 'Matsui|Isao|I|', 'Hamano|Takayuki|T|', 'Okuda|Keiji|K|', 'Tsukamoto|Yasumasa|Y|', 'Matsumoto|Ayumi|A|', 'Shimada|Karin|K|', 'Yasuda|Seiichi|S|', 'Katsuma|Yusuke|Y|', 'Takabatake|Yoshitsugu|Y|', 'Tanaka|Masaru|M|', 'Tanaka|Noriko|N|', 'Mano|Toshiaki|T|', 'Minamino|Tetsuo|T|', 'Sakata|Yasushi|Y|', 'Isaka|Yoshitaka|Y|']
Left ventricular hypertrophy Chronic kidney disease Active vitamin D analog Angiotensin II Calcineurin A Atrogin1