Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure.
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 pressur...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4713444?pdf=render |
| _version_ | 1828340611671916544 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hyeon-Ju Lee |
| collection | DOAJ |
| description | 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.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.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. |
| first_indexed | 2024-04-13T22:58:39Z |
| format | Article |
| id | doaj.art-6c1791b2a75243cc97f2821471c2c680 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T22:58:39Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6c1791b2a75243cc97f2821471c2c6802022-12-22T02:25:56ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01111e014684110.1371/journal.pone.0146841Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure.Hyeon-Ju LeeJi-One KangSung-Moon KimSu-Min JiSo-Yon ParkMarina E KimBaigalmaa JigdenJi Eun LimSue-Yun HwangYoung-Ho LeeBermseok OhRecent 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.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.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.http://europepmc.org/articles/PMC4713444?pdf=render |
| spellingShingle | 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 Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure. PLoS ONE |
| title | Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure. |
| title_full | Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure. |
| title_fullStr | Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure. |
| title_full_unstemmed | Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure. |
| title_short | Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure. |
| title_sort | gene silencing and haploinsufficiency of csk increase blood pressure |
| url | http://europepmc.org/articles/PMC4713444?pdf=render |
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