Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems.
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.
Xiang
Wei
W
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Kong
Juan
J
Chen
Songcang
S
Cao
Li-Ping
LP
Qiao
Guilin
G
Zheng
Wei
W
Liu
Wenhua
W
Li
Xinmin
X
Gardner
David G
DG
Li
Yan Chun
YC
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D018167:Receptors, Calcitriol / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*
D000959:Antihypertensive Agents; D018167:Receptors, Calcitriol; D009320:Atrial Natriuretic Factor; D002216:Captopril