Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse

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Abstract

Our previous studies showed vitamin D deficiency results in increased cardiac contractility, hypertrophy and fibrosis and has profound effects on heart proteomics, structure and function in rat. In this study we found that the heart in vitamin D receptor knockout (VDR-KO) mice is hypertrophied. Six homozygous VDR knockout (−/−), six wild type (+/+) and six heterozygous (+/−) mice were fed a diet containing 2% Ca, 1.25% P and 20% lactose to maintain normal blood calcium and phosphate levels for 12 months. Tail-cuff blood pressure was performed on all mice. Blood pressure determinations showed no differences in systolic or mean blood pressure in WT (+/+), KO (−/−) or HETERO (+/−) mice at 3 and 6 months. However, decreased systolic BP in the KO mice relative to WT at 9 months of age was observed. ECG analysis showed no significant differences in the intact KO, HETERO or WT mice. The mice were killed at 12 months. Heart weight/body weight ratio was 41% (P < .003) greater in the KO mice versus WT and HETERO was 19% (P < .05) increased versus WT. Other VDR-KO tissues did not display hypertrophy. Cross sectional and longitudinal analysis of the heart myofibrils showed highly significant cellular hypertrophy in VDR-KO mice. Trichrome staining of heart tissue showed marked increase in fibrotic lesions in the KO mice. Analysis of plasma renin activity, angiotensin II (AII) and aldosterone levels showed elevated but not significantly different renin activity in KO versus WT and no significant differences in AII or aldosterone levels. Our data do not support the concept that the renin-angiotensin system or hypertension are the factors that elicit these changes. Data presented here reveal that ablation of the VDR signaling system results in profound changes in heart structure. We propose that calcitriol acts directly on the heart as a tranquilizer by blunting cardiomyocyte hypertrophy.

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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