Cardiovascular Research Advance Access originally published online on June 18, 2009
Cardiovascular Research 2009 84(2):292-299; doi:10.1093/cvr/cvp204
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Endothelium-specific overexpression of human IC53 downregulates endothelial nitric oxide synthase activity and elevates systolic blood pressure in mice
1 National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, P.R. China
2 Sino-German Laboratory, Institute of Cardiology and FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
3 Pathophysiology Department, Medical College, Peking University, Beijing, P.R. China
4 Division of Molecular Medicine, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, University of California Los Angeles, Los Angeles, CA, USA
5 Division of Molecular Medicine, Department of Medicine, Cardiovascular Research Laboratories, University of California Los Angeles (UCLA), Los Angeles, CA, USA
* Corresponding authors. Tel: +86 10 65296415; fax: +86 10 65133086. E-mail address: liudp{at}pumc.edu.cn (D.-P.L.); fax: +86 10 68331730/+86 10 68313012. E-mail address: huirutai{at}sglab.org(R.-T.H.)
Aims: Hypertension is one of the major risk factors for cardiovascular diseases. Endothelial cells (ECs) exert important functions in the regulation of blood pressure. A novel gene, IC53, as an isoform of the cyclin-dependent kinase (CDK)-binding protein gene C53, is mainly expressed in vascular ECs and is upregulated in the failing heart of rats. Overexpression of IC53 promotes proliferation of ECs. To examine whether IC53 plays a role in the regulation of vascular tone and blood pressure, we constructed a transgenic (tg) mouse model of the IC53 gene and studied its phenotypes relevant to vascular function.
Methods and results: IC53 cDNA was cloned from a human aorta cDNA library. Using the endothelium-specific VE-cadherin promoter, we constructed tg mice in which IC53 was specifically overexpressed in vascular endothelia and found that the tg mice exhibit elevated systolic blood pressure (SBP) in contrast to the wild-type (wt) controls. Further studies revealed impaired endothelium-dependent vasodilation, reduced nitric oxide (NO) production and decreased endothelial NO synthase (eNOS) expression, and activity in the tg mice. Inhibition of IC53 in human umbilical vein ECs induces upregulation of eNOS activity.
Conclusion: Our results indicate that IC53 participates in the regulation of vascular homeostasis. Endothelium-specific overexpression of IC53 is associated with elevated SBP, which may be in part attributed to the downregulation of eNOS signalling.
KEYWORDS Endothelium; Hypertension; Nitric oxide; Haemodynamics
Time for primary review: 40 days
These authors contributed equally to this article.