Xiang, W. et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am. J. Physiol. Endocrinol. Metab. 288, E125-E132
Department of Medicine, University of Chicago, Chicago, IL 60637, USA. AJP Endocrinology and Metabolism
(Impact Factor: 3.79).
02/2005; 288(1):E125-32. DOI: 10.1152/ajpendo.00224.2004
Our recent studies suggest that 1,25-dihydroxyvitamin D3 functions as an endocrine suppressor of renin biosynthesis. Genetic disruption of the vitamin D receptor (VDR) results in overstimulation of the renin-angiotensin system (RAS), leading to high blood pressure and cardiac hypertrophy. Consistent with the higher heart-to-body weight ratio, the size of left ventricular cardiomyocytes in VDR knockout (KO) mice was markedly increased compared with wild-type (WT) mice. As expected, levels of atrial natriuretic peptide (ANP) mRNA and circulating ANP were also increased in VDRKO mice. Treatment of VDRKO mice with captopril reduced cardiac hypertrophy and normalized ANP expression. To investigate the role of the cardiac RAS in the development of cardiac hypertrophy, the expression of renin, angiotensinogen, and AT-1a receptor in the heart was examined by real-time RT-PCR and immunostaining. In VDRKO mice, the cardiac renin mRNA level was significantly increased, and this increase was further amplified by captopril treatment. Consistently, intense immunostaining was detected in the left ventricle of captopril-treated WT and VDRKO mice by use of an anti-renin antibody. Levels of cardiac angiotensinogen and AT-1a receptor mRNAs were unchanged in the mutant mice. These data suggest that the cardiac hypertrophy seen in VDRKO mice is a consequence of activation of both the systemic and cardiac RAS and support the notion that 1,25-dihydroxyvitamin D(3) regulates cardiac functions, at least in part, through the RAS.
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- "Vitamin D plays an important physiological role in controlling cardiac functions and vitamin D-dependent signaling systems are present in cardiac myocytes and fibroblasts . Vitamin D deficiency has been associated with abnormal cardiac relaxation, proliferation, and increased cardiac renin gene expression , . Previously, we showed that vitamin D therapy prevents the progression to cardiac hypertrophy , and attenuates the development of heart failure in salt sensitive rat model . "
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Altered vitamin D signaling is associated with cardiac dysfunction, but the pathogenic mechanism is not clearly understood. We examine the mechanism and the role of vitamin D signaling in the development of cardiac dysfunction.
Methods and Results
We analyzed 1α-hydroxylase (1α-OHase) knockout (1α-OHase−/−) mice, which lack 1α-OH enzymes that convert the inactive form to hormonally active form of vitamin D. 1α-OHase−/− mice showed modest cardiac hypertrophy at baseline. Induction of pressure overload by transverse aortic constriction (TAC) demonstrated exaggerated cardiac dysfunction in 1α-OHase−/− mice compared to their WT littermates with a significant increase in fibrosis and expression of inflammatory cytokines. Analysis of calcium (Ca2+) transient demonstrated profound Ca2+ handling abnormalities in 1α-OHase−/− mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D3 analog, significantly attenuated defective Ca2+ handling in 1α-OHase−/− CMs. We further delineated the effect of vitamin D deficiency condition to TAC by first correcting the vitamin D deficiency in 1α-OHase−/− mice, followed then by either a daily maintenance dose of vitamin D or vehicle (to achieve vitamin D deficiency) at the time of sham or TAC. In mice treated with vitamin D, there was a significant attenuation of TAC-induced cardiac hypertrophy, interstitial fibrosis, inflammatory markers, Ca2+ handling abnormalities and cardiac function compared to the vehicle treated animals.
Our results provide insight into the mechanism of cardiac dysfunction, which is associated with severely defective Ca2+ handling and defective vitamin D signaling in 1α-OHase−/− mice.
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- "Vitamin D deficiency with dietary calcium deficiency has been associated with impaired fasting glucose and possibly type 2 diabetes mellitus which is a risk factor for cardiovascular disease   which possibly explains the increased prevalence of vitamin D deficiency in our diabetic subgroup. Animal studies have shown that vitamin D regulates RAS by suppressing renin gene expression, deficiency leading to increased renin production and hypertension  , though in our study hypertension was equally distributed between the two groups. Skin pigmentation has a vital role in vitamin D production. "
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Deficiency of 25-hydroxy vitamin D [25(OH)D] is a treatable condition that has been associated with coronary artery disease and many of its risk factors. A practical time to assess for 25(OH)D deficiency, and to initiate treatment, is at the time of an acute myocardial infarction(AMI). The prevalence of 25(OH)D deficiency and the characteristics associated with it in patients with acute myocardial infarction are unknown.
In this study 25(OH)D was assessed in 314 subjects enrolled in a Sri Jayadeva Institute of Cardiovascular Science and Research(SJICS&R). Patients enrolled from December 1, 2011 to February 28, 2012 had serum samples sent to a centralized laboratory for analysis using the ELECYS assay. Normal 25(OH)D levels are ≥ 30 ng/ml, and patients with levels < 30 and > 20 ng/ml were classified as insufficient and those with levels ≤ 20 ng/ml as deficient. Vitamin D and other baseline characteristics were analyzed with T-test and chi-squared test.
Of the 314 enrolled patents, 212 (67.5%) were 25(OH)D deficient and 50(16%) were insufficient, for a total of 83.5% of patients with abnormally low 25(OH)D levels. No significant heterogeneity was observed among age or gender sub groups but 25(OH)D deficiency was more commonly seen in those with lower socioeconomic status, lower activity levels, diabetes, hypercholesterolemia(LDL), hypertriglyceridemia and in smokers.
Vitamin D deficiency is present in most of the patients with acute myocardial infarction and it is associated with many of its risk factors in our study.
Available from: PubMed Central
- "The activated metabolite of 25(OH)D, 1,25-dihydroxyvitamin D (1,25[OH]2D) has been shown to inhibit rennin gene expression . Furthermore, vitamin D receptor null mice exhibit increased renin levels and systemic HTN and ultimately, develop cardiac hypertrophy . In addition, the 1α-hydroxylase enzyme that converts 25(OH)D to 1,25(OH)2D is expressed in a variety of tissues, including human endothelial cells and vascular smooth muscle cells , which suggests another mechanism by which vitamin D may influence the systemic control of BP. "
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ABSTRACT: Recent studies suggest that vitamin D deficiency and cardiometabolic disorders are becoming increasingly more prevalent across multiple populations. However, there is a lack of comprehensive data for Korean adults. We investigated the vitamin D status, the prevalence of vitamin D deficiency and its association with metabolic syndrome (MS) risk in Korean adults aged 20 years or older. The study subjects (n = 18,305) were individuals who participated in the Korean National Health Examination and Nutrition Survey (KNHANES) in 2008-2010. Vitamin D status (25-hydroxyvitamin D [25(OH)D]) was categorized as < 20, 21-29, and ≥ 30 ng/mL, which are the cut-off points for deficiency, insufficiency and normal limits. A wide variety of cardiometabolic risk factors were compared according to the vitamin D status. Vitamin D deficiency was found in 53.9% of men and 70.5% of women. Mean BMI, systolic BP, HbA1c and low density lipoprotein cholesterol (LDL-C) were highest in the vitamin D deficiency group in both genders. Further, the MS was most prevalent in the vitamin D deficiency group in both genders (12.3%, P = 0.002 in men and 9.2%, P < 0.001 in women). Compared to the vitamin D normal group, the adjusted odds ratio (ORs) (95% confidence interval [95% CI]) for MS in the vitamin D deficiency group were 1.46 (1.05-2.02) in men and 1.60 (1.21-2.11) in women, after adjusting for confounding variables. In conclusion, Vitamin D deficiency is a very common health problem in Korean adults and is independently associated with the increasing risk of MS.
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