calcitriol and Cardiomegaly

Targeted gene ablation technology has uncovered biological mechanisms that have led to important therapeutics in humans. In a study by Zhou et al., ablation of the 1alpha-hydroxylase gene led to hypertension, cardiac hypertrophy, and systolic dysfunction, and this cardiac phenotype was rescued with exogenous 1,25-dihydroxyvitamin D administration.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; Cardiomegaly; Gene Targeting; Humans; Hypertension; Mice; Mice, Knockout; Vitamin D

The liganded vitamin D receptor (VDR) is thought to play an important role in controlling cardiac function. Specifically, this system has been implicated as playing an antihypertrophic role in the heart. Despite this, studies of VDR in the heart have been limited in number and scope. In the present study, we used a combination of real-time polymerase chain reaction, Western blot analysis, immunofluorescence, and transient transfection analysis to document the presence of functional VDR in both the myocytes and fibroblasts of the heart, as well as in the intact ventricular myocardium. We also demonstrated the presence of 1-alpha-hydroxylase and 24-hydroxylase in the heart, 2 enzymes involved in the synthesis and metabolism of 1,25 dihydroxyvitamin D. VDR is shown to interact directly with the human B-type natriuretic peptide gene promoter, a surrogate marker of the transcriptional response to hypertrophy. Of note, induction of myocyte hypertrophy either in vitro or in vivo leads to an increase in VDR mRNA and protein levels. Collectively, these findings suggest that the key components required for a functional 1,25 dihydroxyvitamin D-dependent signaling system are present in the heart and that this putatively antihypertrophic system is amplified in the setting of cardiac hypertrophy.

Topics: Animals; Cardiomegaly; Cells, Cultured; Fibroblasts; Gene Expression; Humans; Luciferases; Myocytes, Cardiac; Natriuretic Peptide, Brain; Phosphatidylethanolamines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Calcitriol; Signal Transduction; Vitamin D

To determine whether the cardiovascular effect of 1,25(OH)(2)D is dependent on calcium and/or phosphorus, mice with targeted deletion of the 25(OH)D 1alpha-hydroxylase and their wild-type littermates were fed a normal diet or a diet to rescue the ambient serum calcium and phosphorus levels. Mice on the normal diet were treated daily with vehicle or 1,25(OH)(2)D(3) while mice on the rescue diet received vehicle, captopril or losartan. After four weeks the vehicle-treated knockout mice developed hypertension, cardiac hypertrophy and impaired cardiac function along with an up-regulation of the renin-angiotensin system in both renal and cardiac tissues. Although the serum calcium and phosphorus levels were normalized in knockout mice on the rescue diet, abnormalities in blood pressure, cardiac structure-function and the renin-angiotensin system remained. In contrast, 1,25(OH)(2)D(3) not only normalized serum calcium and phosphorus levels but also normalized blood pressure, cardiac structure-function and the renin-angiotensin system. Treatment of the knockout mice with either captopril or losartan normalized blood pressure and cardiac structure and function although renin expression remained elevated. This study shows that 1,25(OH)2D plays a protective role in the cardiovascular system by repressing the renin-angiotensin system independent of extracellular calcium or phosphorus.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; Antihypertensive Agents; Blood Pressure; Calcium; Captopril; Cardiomegaly; Gene Deletion; Gene Targeting; Hypertension; Losartan; Mice; Mice, Knockout; Myocytes, Cardiac; Phosphorus; Renin-Angiotensin System; Vitamin D