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Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 18, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp204
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Endothelium-specific overexpression of human IC53 downregulates eNOS activity and elevates systolic blood pressure in mice

Ming-Lei Zhuo, MD1,*, Yue Huang, PhD1,*, Jing-Zhou Chen, PhD2,*, Li-Hong Sun, PhD1, Rui-Feng Yang, PhD1, Hou-Zao Chen, PhD1, Xiang Lv, PhD1, Hong-Liang Li, MD PhD1, Yu-Sheng Wei, PhD1, Guang Liu1, Ran Zhang, PhD1, Tie-Min Ma3, Hua Cai, MD PhD4, Ru-Tai Hui, MD PhD2,{dagger}, De-Pei Liu, PhD1,{dagger} and Chih-Chuan Liang, PhD1

1 From National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2 From Sino-German Laboratory, Institute of Cardiology & FuWai hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
3 From Pathophysiology Department, Medical College, Peking University, Beijing, China
4 Division of Molecular Medicine, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, University of California Los Angeles (UCLA), Los Angeles, CA, U.S.A

{dagger} Address correspondence to: De-Pei Liu, PhD. 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. Tel: +86-10-65296415; Fax: +86-10-65133086. Email: liudp{at}pumc.edu.cn, Ru-Tai Hui, MD, PhD. Fax +8610-6833-1730, 8610-6831-3012. Email: huirutai{at}sglab.org

Aim: 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 endothelial cells and is upregulated in the failing heart of rats. Overexpression of IC53 promotes proliferation of endothelial cells. 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 transgenic mice in which IC53 was specifically overexpressed in vascular endothelia and found that the transgenic mice exhibit elevated systolic blood pressure in contrast to the wild-type (wt) controls. Further studies revealed impaired endothelium-dependent vasodilation, reduced nitric oxide production and decreased endothelial nitric oxide synthase (eNOS) expression and activity in the tg mice. Inhibition of IC53 in human umbilical vein endothelial cells induces upregulation of eNOS activity.

Conclusions: Our results indicate that IC53 participates in the regulation of vascular homeostasis. Endothelium-specific overexpression of IC53 is associated with elevated systolic blood pressure, which may be in part attributed to downregulation of eNOS signaling.

KEYWORDS endothelium; hypertension; nitric oxide; hemodynamics

Time for primary review: 40 Days

* The authors contributed equally to this article


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