1. ¹The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, PR of China
2. ²Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, PR of China
3. ³Calcium Research Laboratory, McGill University Health Centre and Department of Medicine, McGill University, Montreal, Quebec, Canada

Correspondence: Dengshun Miao, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu 210029, The People's Republic of China. E-mail: dsmiao@njmu.edu.cn

This work was support by Grant No. 30671009 to DSM from National Natural Science Foundation of China, and by a grant to DG from the Canadian Institutes for Health Research.

⁴These authors contributed equally to this work

Received 5 September 2007; Revised 9 January 2008; Accepted 15 January 2008; Published online 2 April 2008.

Abstract

To determine whether the cardiovascular effect of 1,25(OH)₂D is dependent on calcium and/or phosphorus, mice with targeted deletion of the 25(OH)D 1-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)₂D₃ 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)₂D₃ 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.