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Maxacalcitol (22-Oxacalcitriol (OCT)) Retards Progression of Left Ventricular Hypertrophy with Renal Dysfunction Through Inhibition of Calcineurin-NFAT Activity
- Source :
- Cardiovascular drugs and therapy. 35(2)
- Publication Year :
- 2020
-
Abstract
- 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. 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. 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. Our works indicated that OCT retards progression of LVH through calcineurin-NFAT pathway, which reveal a novel aspect of OCT in attenuating pathological LVH.
- Subjects :
- 0301 basic medicine
Paricalcitol
Male
medicine.medical_specialty
Cell Culture Techniques
030204 cardiovascular system & hematology
Left ventricular hypertrophy
Calcitriol receptor
03 medical and health sciences
0302 clinical medicine
Calcitriol
Pregnancy
Internal medicine
medicine
Animals
Humans
Pharmacology (medical)
Myocytes, Cardiac
cardiovascular diseases
Renal Insufficiency
Rats, Wistar
Aged
Retrospective Studies
Pharmacology
NFATC Transcription Factors
business.industry
Calcineurin
NFAT
General Medicine
Middle Aged
medicine.disease
Angiotensin II
Rats
Disease Models, Animal
030104 developmental biology
Endocrinology
Knockout mouse
Female
Hypertrophy, Left Ventricular
Cardiology and Cardiovascular Medicine
business
medicine.drug
Kidney disease
Subjects
Details
- ISSN :
- 15737241
- Volume :
- 35
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cardiovascular drugs and therapy
- Accession number :
- edsair.doi.dedup.....b4eb1d74c6489401c08e6fa58945fd60