Endothelium-specific overexpression of human IC53 downregulates endothelial nitric oxide synthase activity and elevates systolic blood pressure in mice.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Zhuo
Ming-Lei
ML
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, PR China.
Huang
Yue
Y
Chen
Jing-Zhou
JZ
Sun
Li-Hong
LH
Yang
Rui-Feng
RF
Chen
Hou-Zao
HZ
Lv
Xiang
X
Li
Hong-Liang
HL
Wei
Yu-Sheng
YS
Liu
Guang
G
Zhang
Ran
R
Ma
Tie-Min
TM
Cai
Hua
H
Hui
Ru-Tai
RT
Liu
De-Pei
DP
Liang
Chih-Chuan
CC
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D019332:Endothelin-1 / Q000097:blood; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013599:Systole; D025521:Tumor Suppressor Proteins; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D018797:Cell Cycle Proteins; D019332:Endothelin-1; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D014665:Vasodilator Agents; D000099152:Cadherin 5; C405928:CDK5RAP3 protein, human; C496314:NOS3 protein, human; C496315:Nos3 protein, mouse