Selective gene expression profiling contributes to a better understanding of the molecular pathways underlying the histological changes observed after RHMVL.
Gene expression
Liver resection
Portal hypertension
Vasoactive drug
Journal
BMC medical genomics
ISSN: 1755-8794
Titre abrégé: BMC Med Genomics
Pays: England
ID NLM: 101319628
Informations de publication
Date de publication:
07 10 2022
07 10 2022
Historique:
received:
14
01
2022
accepted:
21
09
2022
entrez:
7
10
2022
pubmed:
8
10
2022
medline:
12
10
2022
Statut:
epublish
Résumé
In previous studies, five vasoactive drugs were investigated for their effect on the recovery process after extended liver resection without observing relevant improvements. We hypothesized that an analysis of gene expression could help to identify potentially druggable pathways and could support the selection of promising drug candidates. Liver samples obtained from rats after combined 70% partial hepatectomy and right median hepatic vein ligation (n = 6/group) sacrificed at 0 h, 24 h, 48 h, and 7days were selected for this study. Liver samples were collected from differentially perfused regions of the median lobe (obstruction-zone, border-zone, normal-zone). Gene expression profiling of marker genes regulating hepatic hemodynamics, vascular remodeling, and liver regeneration was performed with microfluidic chips. We used 3 technical replicates from each sample. Raw data were normalized using LEMming and differentially expressed genes were identified using LIMMA. The strongest differences were found in obstruction-zone at 24 h and 48 h postoperatively compared to all other groups. mRNA expression of marker genes from hepatic hemodynamics pathways (iNOS,Ptgs2,Edn1) was most upregulated. These upregulated genes suggest a strong vasoconstrictive effect promoting arterial hypoperfusion in the obstruction-zone. Reducing iNOS expression using selective iNOS inhibitors seems to be a promising approach to promote vasodilation and liver regeneration.
Sections du résumé
BACKGROUND
In previous studies, five vasoactive drugs were investigated for their effect on the recovery process after extended liver resection without observing relevant improvements. We hypothesized that an analysis of gene expression could help to identify potentially druggable pathways and could support the selection of promising drug candidates.
METHODS
Liver samples obtained from rats after combined 70% partial hepatectomy and right median hepatic vein ligation (n = 6/group) sacrificed at 0 h, 24 h, 48 h, and 7days were selected for this study. Liver samples were collected from differentially perfused regions of the median lobe (obstruction-zone, border-zone, normal-zone). Gene expression profiling of marker genes regulating hepatic hemodynamics, vascular remodeling, and liver regeneration was performed with microfluidic chips. We used 3 technical replicates from each sample. Raw data were normalized using LEMming and differentially expressed genes were identified using LIMMA.
RESULTS
The strongest differences were found in obstruction-zone at 24 h and 48 h postoperatively compared to all other groups. mRNA expression of marker genes from hepatic hemodynamics pathways (iNOS,Ptgs2,Edn1) was most upregulated.
CONCLUSION
These upregulated genes suggest a strong vasoconstrictive effect promoting arterial hypoperfusion in the obstruction-zone. Reducing iNOS expression using selective iNOS inhibitors seems to be a promising approach to promote vasodilation and liver regeneration.
Identifiants
pubmed: 36207717
doi: 10.1186/s12920-022-01364-z
pii: 10.1186/s12920-022-01364-z
pmc: PMC9547442
doi:
Substances chimiques
RNA, Messenger
0
Cyclooxygenase 2
EC 1.14.99.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
211Informations de copyright
© 2022. The Author(s).
Références
Gut. 2002 Apr;50(4):571-81
pubmed: 11889082
Rom J Morphol Embryol. 2014;55(2 Suppl):539-43
pubmed: 25178323
Hepatology. 2006 Feb;43(2 Suppl 1):S45-53
pubmed: 16447274
Biochem Biophys Res Commun. 1992 Jul 31;186(2):867-73
pubmed: 1323294
Transplantation. 1989 Sep;48(3):438-43
pubmed: 2675403
Transplantation. 2003 Mar 15;75(5):703-10
pubmed: 12640313
Transplantation. 2002 May 15;73(9):1439-46
pubmed: 12023622
Hepatol Int. 2018 Feb;12(Suppl 1):1-10
pubmed: 29064029
Am J Physiol. 1996 Jan;270(1 Pt 2):H7-15
pubmed: 8769728
Shock. 1999 May;11(5):325-9
pubmed: 10353537
Fukuoka Igaku Zasshi. 2013 Sep;104(9):282-9
pubmed: 24364263
Best Pract Res Clin Gastroenterol. 2008;22(2):279-94
pubmed: 18346684
J Hepatol. 2009 Mar;50(3):604-20
pubmed: 19157625
Arch Immunol Ther Exp (Warsz). 2015 Feb;63(1):41-52
pubmed: 25288367
Cancer Manag Res. 2019 Aug 26;11:8005-8022
pubmed: 31692584
FEBS Lett. 1996 Mar 11;382(1-2):101-4
pubmed: 8612727
Biochem Pharmacol. 2020 May;175:113847
pubmed: 32035080
PLoS One. 2015 Nov 02;10(11):e0141877
pubmed: 26523932
Toxicol Lett. 2003 Oct 15;144(3):279-88
pubmed: 12927346
Hepatology. 2000 Apr;31(4):937-47
pubmed: 10733551
J Appl Physiol (1985). 2002 Mar;92(3):1152-8
pubmed: 11842053
Transplantation. 1999 Jan 27;67(2):321-7
pubmed: 10075602
Annu Rev Biochem. 1995;64:721-62
pubmed: 7574499
J Biol Chem. 1997 Jan 3;272(1):601-8
pubmed: 8995303
Inflamm Res. 1996 Jun;45(6):272-6
pubmed: 8814457
Physiol Rev. 2009 Oct;89(4):1269-339
pubmed: 19789382
Transplantation. 2003 Mar 15;75(5):673-8
pubmed: 12640308
Nitric Oxide. 2007 Nov-Dec;17(3-4):126-33
pubmed: 17889572
Am J Physiol. 1996 Nov;271(5 Pt 1):C1424-37
pubmed: 8944624
J Hepatobiliary Pancreat Sci. 2020 Nov;27(11):799-809
pubmed: 32897590
Nutrition. 1998 Apr;14(4):376-90
pubmed: 9591311
Oncotarget. 2017 Jun 16;8(39):65397-65406
pubmed: 29029439
Am J Physiol. 1999 May;276(5):G1069-73
pubmed: 10329995
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
J Gastroenterol Hepatol. 2008 Jul;23(7 Pt 2):e231-5
pubmed: 17683476
Dig Dis Sci. 1994 Feb;39(2):245-52
pubmed: 7906221
J Cell Physiol. 2007 Nov;213(2):286-300
pubmed: 17559071
J Surg Res. 2005 May 1;125(1):78-87
pubmed: 15836854
BMC Pharmacol Toxicol. 2017 Jun 26;18(1):50
pubmed: 28651622
Pharmacol Rep. 2012;64(3):511-20
pubmed: 22814004
Am J Physiol Cell Physiol. 2002 Feb;282(2):C395-402
pubmed: 11788351
J Am Coll Surg. 2013 Mar;216(3):353-62
pubmed: 23318119
Nutrients. 2020 Aug 28;12(9):
pubmed: 32872239
Am J Transplant. 2011 Nov;11(11):2342-52
pubmed: 21831159
J Biomech. 2017 Jan 4;50:202-208
pubmed: 27890535
Transplantation. 2014 May 27;97(10):1009-18
pubmed: 24770620
J Gastroenterol Hepatol. 2019 Aug;34(8):1276-1286
pubmed: 30828863
J Viral Hepat. 2014;21(9):671-9
pubmed: 24215170
Nitric Oxide. 2013 Apr 1;30:9-16
pubmed: 23348570
Br J Surg. 2008 Jun;95(6):785-92
pubmed: 18412296
J Surg Res. 2009 Aug;155(2):311-7
pubmed: 19482311
Nephrol Dial Transplant. 2000 Mar;15(3):339-46
pubmed: 10692519
Science. 1992 Dec 18;258(5090):1898-902
pubmed: 1281928
Transplantation. 2008 Mar 15;85(5):748-56
pubmed: 18337670
Liver Int. 2020 Feb;40 Suppl 1:122-127
pubmed: 32077610
Drug Chem Toxicol. 2021 Mar;44(2):215-221
pubmed: 30691306
World J Surg. 2007 Mar;31(3):549-55
pubmed: 17308852
Gastroenterology. 1985 Nov;89(5):1092-6
pubmed: 4043666
Ann Hepatol. 2012 Sep-Oct;11(5):636-47
pubmed: 22947523
J Hepatol. 2000 May;32(5):798-804
pubmed: 10845667
Semin Liver Dis. 1999;19(4):383-96
pubmed: 10643624
Hepatology. 2007 Mar;45(3):817-25
pubmed: 17326208
Free Radic Biol Med. 2012 Jul 15;53(2):250-9
pubmed: 22609250
Pflugers Arch. 2001 Jul;442(4):479-86
pubmed: 11510878
J Clin Pathol. 2004 Apr;57(4):350-4
pubmed: 15047734
Am J Physiol. 1985 Nov;249(5 Pt 1):G549-56
pubmed: 3904482
Transplant Proc. 2014 May;46(4):1112-6
pubmed: 24815141
Eur J Pharmacol. 1997 Jun 11;328(2-3):175-82
pubmed: 9218699
J Biol Chem. 1997 Dec 5;272(49):31138-48
pubmed: 9388267
Semin Liver Dis. 2001 Aug;21(3):337-49
pubmed: 11586464
Trends Pharmacol Sci. 2015 Aug;36(8):524-36
pubmed: 26027855
Expert Opin Emerg Drugs. 2016 Jun;21(2):167-81
pubmed: 27148904
Metab Brain Dis. 2002 Dec;17(4):325-34
pubmed: 12602509
FASEB J. 2002 Dec;16(14):1994-6
pubmed: 12397095
PLoS One. 2015 Sep 01;10(9):e0135852
pubmed: 26325269
J Clin Gastroenterol. 2007 Nov-Dec;41 Suppl 3:S259-61
pubmed: 17975474
Semin Cancer Biol. 2021 Jun;71:86-97
pubmed: 32532594
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17161-6
pubmed: 12482944
World J Gastroenterol. 2012 Mar 21;18(11):1166-75
pubmed: 22468079
Surgery. 2003 Oct;134(4):647-53; discussion 654-5
pubmed: 14605626