title: Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Hyeon-Ju
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Ji-One
authors.initials: JO
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Sung-Moon
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Su-Min
authors.initials: SM
authors.lastname: Ji
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: So-Yon
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Baigalmaa
authors.initials: B
authors.lastname: Jigden
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Lim
authors.affiliation: Department of Chemical Engineering, College of Engineering, HanKyong National University, Ansung-Si, Gyeonggi-Do, Korea.
authors.forename: Sue-Yun
authors.initials: SY
authors.lastname: Hwang
authors.affiliation: Department of Physiology, College of Medicine, Yonsei University, Seoul, Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Bermseok
authors.initials: B
authors.lastname: Oh
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001794:Blood Pressure; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D002874:Chromosome Mapping; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D057895:Haploinsufficiency; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics*
chemical_list: C102315:Npy6r protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011964:Receptors, Gastrointestinal Hormone; D017476:Receptors, Neuropeptide Y; D019388:Cytochrome P-450 CYP1A2; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D017346:Protein Serine-Threonine Kinases