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Gene silencing and haploinsufficiency of Csk increase blood pressure

 Hyeon-Ju Lee  ;  Ji-One Kang  ;  Sung-Moon Kim  ;  Su-Min Ji  ;  So-Yon Park  ;  Marina E. Kim  ;  Baigalmaa Jigden  ;  Ji Eun Lim  ;  Sue-Yun Hwang  ;  Young-Ho Lee  ;  Bermseok Oh 
 PLOS ONE, Vol.11(1) : e0146841, 2016 
Journal Title
Issue Date
Animals ; Aorta/pathology ; Blood Pressure* ; Cell Line ; Chromosome Mapping ; Cytochrome P-450 CYP1A2/genetics ; Female ; Gene Silencing* ; Haploinsufficiency* ; Humans ; Hypertension/genetics ; Hypertension/therapy ; Mice ; Mice, Inbred BALB C ; Muscle, Smooth, Vascular/cytology ; Polymorphism, Single Nucleotide ; Protein-Serine-Threonine Kinases/genetics ; Quantitative Trait Loci ; RNA, Messenger/metabolism ; RNA, Small Interfering/metabolism ; Receptors, Gastrointestinal Hormone/metabolism ; Receptors, Neuropeptide Y/metabolism ; src-Family Kinases/genetics*
OBJECTIVE: Recent genome-wide association studies have identified 33 human genetic loci that influence blood pressure. The 15q24 locus is one such locus that has been confirmed in Asians and Europeans. There are 21 genes in the locus within a 1-Mb boundary, but a functional link of these genes to blood pressure has not been reported. We aimed to identify a causative gene for blood pressure change in the 15q24 locus.
METHODS AND RESULTS: CSK and ULK3 were selected as candidate genes based on eQTL analysis studies that showed the association between gene transcript levels and the lead SNP (rs1378942). Injection of siRNAs for mouse homologs Csk, Ulk3, and Cyp1a2 (negative control) showed reduced target gene mRNA levels in vivo. However, Csk siRNA only increased blood pressure while Ulk3 and Cyp1a2 siRNA did not change it. Further, blood pressure in Csk+/- heterozygotes was higher than in wild-type, consistent with what we observed in Csk siRNA-injected mice. We confirmed that haploinsufficiency of Csk increased the active form of Src in Csk+/- mice aorta. We also showed that inhibition of Src by PP2, a Src inhibitor decreased high blood pressure in Csk+/- mice and the active Src in Csk+/- mice aorta and in Csk knock-down vascular smooth muscle cells, suggesting blood pressure regulation by Csk through Src.
CONCLUSIONS: Our study demonstrates that Csk is a causative gene in the 15q24 locus and regulates blood pressure through Src, and these findings provide a novel therapeutic target for the treatment of hypertension.
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1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Lee, Young Ho(이영호) ORCID logo https://orcid.org/0000-0002-5749-1045
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