Vitamin D(2) supplementation induces the development of aortic stenosis in rabbits: interactions with endothelial function and thioredoxin-interacting protein.
Understanding of the pathophysiology of aortic valve stenosis (AVS) and finding potentially effective treatments are impeded by the lack of suitable AVS animal models. A previous study demonstrated the development of AVS in rabbits with vitamin D(2) and cholesterol supplementation without any hemodynamic changes in the cholesterol supplemented group alone. The current study aimed to determine whether AVS develops in an animal model with vitamin D(2) supplementation alone, and to explore pathophysiological mechanisms underlying this process. The effects of 8 weeks' treatment with vitamin D(2) alone (n=8) at 25,000 IU/4 days weekly on aortic valve structure and function were examined in male New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV(BS)), transvalvular velocity, and transvalvular pressure gradient were utilized to quantitate changes in valve structure and function. Valvular histology/immunochemistry and function were examined after 8 weeks. Changes in valves were compared with those in endothelial function and in valvular measurement of thioredoxin-interacting protein (TXNIP), a marker/mediator of reactive oxygen species-induced oxidative stress. Vitamin D(2) treated rabbits developed AVS with increased AV(BS) (17.6+/-1.4 dB vs 6.7+/-0.8 dB, P<0.0001), increased transvalvular velocity and transvalvular pressure gradient (both P<0.01 via 2-way ANOVA) compared to the control group. There was associated valve calcification, lipid deposition and macrophage infiltration. Endothelial function was markedly impaired, and intravalvular TXNIP concentration increased. In this model, vitamin D(2) induces the development of AVS with histological features similar to those of early AVS in humans and associated endothelial dysfunction/redox stress. AVS development may result from the loss of nitric oxide suppression of TXNIP expression.
Ngo
Doan T M
DT
Cardiology Unit, The Queen Elizabeth Hospital, Department of Medicine, The University of Adelaide, Australia.
Stafford
Irene
I
Kelly
Darren J
DJ
Sverdlov
Aaron L
AL
Wuttke
Ronald D
RD
Weedon
Helen
H
Nightingale
Angus K
AK
Rosenkranz
Anke C
AC
Smith
Malcolm D
MD
Chirkov
Yuliy Y
YY
Kennedy
Jennifer A
JA
Horowitz
John D
JD
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001024:Aortic Valve Stenosis / Q000139:chemically induced* / Q000503:physiopathology; D002352:Carrier Proteins / Q000032:analysis / Q000502:physiology*; D004195:Disease Models, Animal; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004872:Ergocalciferols / Q000008:administration & dosage*; D006937:Hypercholesterolemia / Q000150:complications; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D018384:Oxidative Stress; D011817:Rabbits
D002352:Carrier Proteins; D004872:Ergocalciferols; C486715:TXNIP protein, human