PMID- 36499651
OWN - NLM
STAT- MEDLINE
DCOM- 20221216
LR  - 20221221
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 23
DP  - 2022 Dec 5
TI  - The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Attenuates Transforming 
      Growth Factor beta1-Induced Myofibroblast Differentiation of Human Corneal 
      Keratocytes.
LID - 10.3390/ijms232315325 [doi]
LID - 15325
AB  - Corneal transparency, necessary for vision and depending on the high organization 
      of stromal extracellular matrix, is maintained by keratocytes. Severe or 
      continuous corneal injuries determine exaggerated healing responses resulting in 
      the formation of irreversible fibrotic scars and vision impairment. Soluble 
      guanylate cyclase (sGC) stimulation demonstrated antifibrotic effects in both 
      experimental fibrosis and human lung and skin fibroblasts. Here, we assessed 
      whether sGC stimulation with BAY 41-2272 could attenuate transforming growth 
      factor beta1 (TGFbeta1)-induced myofibroblast differentiation of human corneal 
      keratocytes. Cells were challenged with TGFbeta1, with/without BAY 41-2272 
      preincubation, and subsequently assessed for viability, proliferation, migration, 
      chemoinvasion, as well for the expression of myofibroblast/fibroblast activation 
      markers and contractile abilities. Treatment with BAY 41-2272 did not affect 
      keratocyte viability, while preincubation of cells with the sGC stimulator was 
      able to inhibit TGFbeta1-induced proliferation, wound healing capacity, and 
      invasiveness. BAY 41-2272 was also able to attenuate TGFbeta1-induced 
      myofibroblast-like profibrotic phenotype of keratocytes, as demonstrated by the 
      significant decrease in ACTA2, COL1A1, COL1A2, FN1 and PDPN gene expression, as 
      well as in alpha-smooth muscle actin, alpha-1 chain of type I collagen, podoplanin, 
      vimentin and N-cadherin protein expression. Finally, BAY 41-2272 significantly 
      counteracted the TGFbeta1-induced myofibroblast-like ability of keratocytes to 
      contract collagen gels, reduced phosphorylated Smad3 protein levels, and 
      attenuated gene expression of proinflammatory cytokines. Collectively, our data 
      show for the first time that BAY 41-2272 is effective in counteracting 
      keratocyte-to-myofibroblast transition, thus providing the rationale for the 
      development of sGC stimulators as novel promising modulators of corneal scarring 
      and fibrosis.
FAU - Rosa, Irene
AU  - Rosa I
AUID- ORCID: 0000-0001-6352-0175
AD  - Section of Anatomy and Histology, Department of Experimental and Clinical 
      Medicine, University of Florence, 50134 Florence, Italy.
FAU - Fioretto, Bianca Saveria
AU  - Fioretto BS
AUID- ORCID: 0000-0001-9275-7593
AD  - Section of Anatomy and Histology, Department of Experimental and Clinical 
      Medicine, University of Florence, 50134 Florence, Italy.
AD  - Section of Internal Medicine, Department of Experimental and Clinical Medicine, 
      University of Florence, 50134 Florence, Italy.
FAU - Romano, Eloisa
AU  - Romano E
AUID- ORCID: 0000-0003-2744-8625
AD  - Section of Internal Medicine, Department of Experimental and Clinical Medicine, 
      University of Florence, 50134 Florence, Italy.
FAU - Buzzi, Matilde
AU  - Buzzi M
AD  - Eye Clinic, Careggi Hospital, Department of Neurosciences, Psychology, 
      Pharmacology and Child Health (NEUROFARBA), University of Florence, 50134 
      Florence, Italy.
FAU - Mencucci, Rita
AU  - Mencucci R
AUID- ORCID: 0000-0003-1856-6363
AD  - Eye Clinic, Careggi Hospital, Department of Neurosciences, Psychology, 
      Pharmacology and Child Health (NEUROFARBA), University of Florence, 50134 
      Florence, Italy.
FAU - Marini, Mirca
AU  - Marini M
AUID- ORCID: 0000-0002-1934-0414
AD  - Section of Anatomy and Histology, Department of Experimental and Clinical 
      Medicine, University of Florence, 50134 Florence, Italy.
FAU - Manetti, Mirko
AU  - Manetti M
AUID- ORCID: 0000-0003-3956-8480
AD  - Section of Anatomy and Histology, Department of Experimental and Clinical 
      Medicine, University of Florence, 50134 Florence, Italy.
AD  - Imaging Platform, Department of Experimental and Clinical Medicine, University of 
      Florence, 50134 Florence, Italy.
LA  - eng
PT  - Journal Article
DEP - 20221205
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (Collagen Type I, alpha2 Subunit)
RN  - 0 
      (3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine)
RN  - EC 4.6.1.2 (Soluble Guanylyl Cyclase)
RN  - 0 (Actins)
SB  - IM
MH  - Humans
MH  - *Corneal Keratocytes/metabolism
MH  - Transforming Growth Factor beta1/pharmacology/metabolism
MH  - Soluble Guanylyl Cyclase/metabolism
MH  - Cells, Cultured
MH  - Myofibroblasts/metabolism
MH  - Cell Differentiation
MH  - Actins/metabolism
MH  - Fibroblasts/metabolism
MH  - *Corneal Injuries/metabolism
MH  - Fibrosis
PMC - PMC9737374
OTO - NOTNLM
OT  - corneal fibrosis
OT  - human cornea
OT  - keratocytes
OT  - myofibroblasts
OT  - soluble guanylate cyclase stimulator
OT  - transforming growth factor beta1
COIS- The authors declare no conflict of interest.
EDAT- 2022/12/12 06:00
MHDA- 2022/12/15 06:00
PMCR- 2022/12/05
CRDT- 2022/12/11 01:21
PHST- 2022/11/04 00:00 [received]
PHST- 2022/12/01 00:00 [revised]
PHST- 2022/12/03 00:00 [accepted]
PHST- 2022/12/11 01:21 [entrez]
PHST- 2022/12/12 06:00 [pubmed]
PHST- 2022/12/15 06:00 [medline]
PHST- 2022/12/05 00:00 [pmc-release]
AID - ijms232315325 [pii]
AID - ijms-23-15325 [pii]
AID - 10.3390/ijms232315325 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Dec 5;23(23):15325. doi: 10.3390/ijms232315325.