PMID- 35315960
OWN - NLM
STAT- MEDLINE
DCOM- 20220422
LR  - 20220422
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 36
IP  - 4
DP  - 2022 Apr
TI  - Homozygous whole body Cbs knockout in adult mice features minimal pathology 
      during ageing despite severe homocysteinemia.
PG  - e22260
LID - 10.1096/fj.202101550R [doi]
AB  - Deficiencies in Cystathionine-beta-synthase (CBS) lead to hyperhomocysteinemia 
      (HHCy), which is considered a risk factor for cardiovascular, bone and 
      neurological disease. Moreover, CBS is important for the production of cysteine, 
      hydrogen sulfide (H(2) S) and glutathione. Studying the biological role of CBS in 
      adult mice has been severely hampered by embryological disturbances and perinatal 
      mortality. To overcome these issues and assess the effects of whole-body CBS 
      deficiency in adult mice, we engineered and characterized a Cre-inducible Cbs 
      knockout model during ageing. No perinatal mortality occurred before Cbs(-/-) 
      induction at 10 weeks of age. Mice were followed until 90 weeks of age and 
      ablation of Cbs was confirmed in liver and kidney but not in brain. Severe HHCy 
      was observed in Cbs(-/-) (289 +/- 58 microM) but not in Cbs(+/-) or control mice 
      (<10 microM). Cbs(-/-) showed impaired growth, facial alopecia, endothelial 
      dysfunction in absence of increased mortality, and signs of liver or kidney 
      damage. CBS expression in skin localized to sebaceous glands and epidermis, 
      suggesting local effects of Cbs(-/-) on alopecia. Cbs(-/-) showed increased 
      markers of oxidative stress and senescence but expression of other H(2) S 
      producing enzymes (CSE and 3-MST) was not affected. CBS deficiency severely 
      impaired H(2) S production capacity in liver, but not in brain or kidney. In 
      summary, Cbs(-/-) mice presented a mild phenotype without mortality despite 
      severe HHCy. The findings demonstrate that HHCy is not directly linked to 
      development of end organ damage.
CI  - (c) 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on 
      behalf of Federation of American Societies for Experimental Biology.
FAU - Nakladal, D
AU  - Nakladal D
AUID- ORCID: 0000-0003-0900-0130
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Center Groningen, Groningen, The Netherlands.
FAU - Lambooy, S P H
AU  - Lambooy SPH
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Center Groningen, Groningen, The Netherlands.
FAU - Misuth, S
AU  - Misuth S
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Center Groningen, Groningen, The Netherlands.
AD  - Department of Pharmacology & Toxicology, Faculty of Pharmacy, Comenius University 
      in Bratislava, Bratislava, Slovakia.
FAU - Cepcova, D
AU  - Cepcova D
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Center Groningen, Groningen, The Netherlands.
AD  - Department of Pharmacology & Toxicology, Faculty of Pharmacy, Comenius University 
      in Bratislava, Bratislava, Slovakia.
FAU - Joschko, C P
AU  - Joschko CP
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Center Groningen, Groningen, The Netherlands.
FAU - van Buiten, A
AU  - van Buiten A
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Center Groningen, Groningen, The Netherlands.
FAU - Goris, M
AU  - Goris M
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Center Groningen, Groningen, The Netherlands.
FAU - Hoogstra-Berends, F
AU  - Hoogstra-Berends F
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Center Groningen, Groningen, The Netherlands.
FAU - Kloosterhuis, N J
AU  - Kloosterhuis NJ
AD  - Department of Pediatrics, University of Groningen, University Medical Center 
      Groningen, Groningen, The Netherlands.
FAU - Huijkman, N
AU  - Huijkman N
AD  - iPSC/CRISPR Center Groningen, University of Groningen, University Medical Center 
      Groningen, Groningen, The Netherlands.
FAU - van de Sluis, B
AU  - van de Sluis B
AD  - Department of Pediatrics, University of Groningen, University Medical Center 
      Groningen, Groningen, The Netherlands.
AD  - iPSC/CRISPR Center Groningen, University of Groningen, University Medical Center 
      Groningen, Groningen, The Netherlands.
FAU - Diercks, G F
AU  - Diercks GF
AD  - Department of Dermatology, Center for Blistering Diseases, University of 
      Groningen, University Medical Center Groningen, Groningen, The Netherlands.
FAU - Buikema, J H
AU  - Buikema JH
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Center Groningen, Groningen, The Netherlands.
FAU - Henning, R H
AU  - Henning RH
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Center Groningen, Groningen, The Netherlands.
FAU - Deelman, L E
AU  - Deelman LE
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Center Groningen, Groningen, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
RN  - YY9FVM7NSN (Hydrogen Sulfide)
RN  - Homocysteinemia
SB  - IM
MH  - Aging
MH  - Alopecia
MH  - Animals
MH  - Cystathionine beta-Synthase/genetics/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - *Homocystinuria/metabolism
MH  - *Hydrogen Sulfide/metabolism
MH  - *Hyperhomocysteinemia/genetics/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Pregnancy
OTO - NOTNLM
OT  - cystathionine beta synthase deficiency
OT  - hydrogen sulfide
OT  - hyperhomocysteinemia
OT  - inducible mouse model
OT  - vascular dysfunction
EDAT- 2022/03/23 06:00
MHDA- 2022/04/23 06:00
CRDT- 2022/03/22 12:12
PHST- 2022/02/17 00:00 [revised]
PHST- 2021/10/19 00:00 [received]
PHST- 2022/03/07 00:00 [accepted]
PHST- 2022/03/22 12:12 [entrez]
PHST- 2022/03/23 06:00 [pubmed]
PHST- 2022/04/23 06:00 [medline]
AID - 10.1096/fj.202101550R [doi]
PST - ppublish
SO  - FASEB J. 2022 Apr;36(4):e22260. doi: 10.1096/fj.202101550R.