The Journal of Steroid Biochemistry and Molecular Biology
Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse
Introduction
Several laboratories have characterized the effects that modification of the vitamin D endocrine system has on cardiac muscle structure and function. We showed that vitamin D3 deficiency alters rat myocardial morphology, ECM and function [1], [2], [3]. Our initial studies revealed that large and statistically significant increases in ventricular pressure development (+dP/dt) are observed in perfused hearts from young (9 weeks old) vitamin D3-deficient rats compared to hearts from vitamin D3-sufficient rats. A mechanism by which myocardial contractility can be increased is by raising intracellular calcium concentrations. We showed that 9-week-old vitamin D3-deficient rats had an increase of L-type calcium channels and post rest contraction response, a measure of sarcoplasmic reticulum calcium uptake [2]. Heart failure affects nearly 5 million people in the United States alone and at present no single unifying hypothesis can account for the etiology of this disease. However, it is known that neuroendocrine factors and cytokines are associated with HF and that left ventricular remodeling is an important determinant in the progression to heart failure. Reduced levels of the most active vitamin D metabolite, 1,25-dihydroxyvitamin D3 are associated with an increased risk of heart failure and reports also indicate ventricular function is compromised and a dilated cardiomyopathy develops in pediatric patients with rickets caused by a vitamin D deficiency [4]. Thus, the following study of the cardiovascular effects of VDR ablation in mice is important and relevant to human disease. A recent study by Xiang et al. suggests that activation of both systemic and cardiac RAS plays an important role in the development of cardiac hypertrophy in VDR(−/−) mice [5].
Section snippets
Mouse breeding, housing and feeding
Wild-type [WT] VDR (+/+), heterozygous (+/−) and VDRKO (−/−) mice were produced from VDR(+/−) originally the generous gift of Dr. Marie Demay, Mass General Hospitals. All mice, breeders and offspring were housed in the University of Michigan Laboratory Animal facility with a 12:12-h light-dark cycle and fed a rodent chow containing 2% Ca, 1.25% phosphorus and 20% lactose. Age-matched WT(+/+), heterozygous (+/−) and VDRKO(−/−) mice were genotyped and used in this study.
Measurement of myocardial heart weight/body weight ratio
Mice were weighed and then
Results
Fig. 1 shows the heart weight body weight ratio of VDR wild type (+/+), knockout (−/−) and heterozygous (+/−) mice. There was a significant 41% [P < .005] increased HW/BW ratio for the VDRKO hearts relative to the VDRWT mice hearts. Heterozygous (+/−) mice had an increased 14% [P < .05] HW/BW ratio relative to WT. Fig. 2 is data obtained from the analysis of liver, kidney, brain and tibia for organ weight/body weight ratios for the KO(−/−), WT(+/+) and HET(+/−) mice. The data show that for liver,
Discussion
Results from the present study demonstrate the effects of ablation of the vitamin D receptor and signaling on adult mouse heart structure. The data reveal that profound cardiac hypertrophy is apparent at 12 months of age for the VDRKO mouse. Relative to our previous studies with vitamin D deficient rats the increase in heart weight to body weight was much greater in the VDRKO mouse (41%) relative to the level of hypertrophy in 9- or 18-month-old vitamin D deficient rat (∼18%) initially reported
Acknowledgements
This work was supported by the National Institutes of Healthgrant # HL074894 and the NIH funded Diabetes, Cancer, Organogenesis and Bone Centers at the University of Michigan Medical School.
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