PMID- 38334606
OWN - NLM
STAT- MEDLINE
DCOM- 20240214
LR  - 20240214
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 13
IP  - 3
DP  - 2024 Jan 24
TI  - Moderate Elevation of Homocysteine Induces Endothelial Dysfunction through 
      Adaptive UPR Activation and Metabolic Rewiring.
LID - 10.3390/cells13030214 [doi]
LID - 214
AB  - Elevation of the intermediate amino acid metabolite Homocysteine (Hcy) causes 
      Hyperhomocysteinemia (HHcy), a metabolic disorder frequently associated with 
      mutations in the methionine-cysteine metabolic cycle as well as with nutritional 
      deficiency and aging. The previous literature suggests that HHcy is a strong risk 
      factor for cardiovascular diseases. Severe HHcy is well-established to correlate 
      with vascular pathologies primarily via endothelial cell death. Though moderate 
      HHcy is more prevalent and associated with an increased risk of cardiovascular 
      abnormalities in later part of life, its precise role in endothelial physiology 
      is largely unknown. In this study, we report that moderate elevation of Hcy 
      causes endothelial dysfunction through impairment of their migration and 
      proliferation. We established that unlike severe elevation of Hcy, moderate HHcy 
      is not associated with suppression of endothelial VEGF/VEGFR transcripts and ROS 
      induction. We further showed that moderate HHcy induces a sub-lethal ER stress 
      that causes defective endothelial migration through abnormal actin cytoskeletal 
      remodeling. We also found that sub-lethal increase in Hcy causes endothelial 
      proliferation defect by suppressing mitochondrial respiration and concomitantly 
      increases glycolysis to compensate the consequential ATP loss and maintain 
      overall energy homeostasis. Finally, analyzing a previously published microarray 
      dataset, we confirmed that these hallmarks of moderate HHcy are conserved in 
      adult endothelial cells as well. Thus, we identified adaptive UPR and metabolic 
      rewiring as two key mechanistic signatures in moderate HHcy-associated 
      endothelial dysfunction. As HHcy is clinically associated with enhanced vascular 
      inflammation and hypercoagulability, identifying these mechanistic pathways may 
      serve as future targets to regulate endothelial function and health.
FAU - Chatterjee, Barun
AU  - Chatterjee B
AUID- ORCID: 0000-0001-6081-0855
AD  - CSIR-Institute of Genomics & Integrative Biology, New Delhi 110025, India.
AD  - Academy of Scientific & Innovative Research, Ghaziabad 201002, India.
FAU - Fatima, Fabeha
AU  - Fatima F
AD  - CSIR-Institute of Genomics & Integrative Biology, New Delhi 110025, India.
FAU - Seth, Surabhi
AU  - Seth S
AD  - CSIR-Institute of Genomics & Integrative Biology, New Delhi 110025, India.
AD  - Academy of Scientific & Innovative Research, Ghaziabad 201002, India.
FAU - Sinha Roy, Soumya
AU  - Sinha Roy S
AD  - CSIR-Institute of Genomics & Integrative Biology, New Delhi 110025, India.
AD  - Academy of Scientific & Innovative Research, Ghaziabad 201002, India.
LA  - eng
GR  - BSC0122/Council of Scientific and Industrial Research/
PT  - Journal Article
DEP - 20240124
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0LVT1QZ0BA (Homocysteine)
SB  - IM
MH  - Humans
MH  - Endothelial Cells/metabolism
MH  - Homocysteine/metabolism
MH  - Cell Death
MH  - *Vascular Diseases/metabolism
MH  - *Cardiovascular Diseases/metabolism
PMC - PMC10854856
OTO - NOTNLM
OT  - ER stress
OT  - TCA cycle
OT  - actin cytoskeleton
OT  - angiogenesis
OT  - endothelial cell
OT  - glycolysis
OT  - homocysteine
OT  - mitochondria
OT  - zebrafish
COIS- The authors declare no conflict of interest.
EDAT- 2024/02/09 12:44
MHDA- 2024/02/10 14:43
PMCR- 2024/01/24
CRDT- 2024/02/09 10:14
PHST- 2023/11/06 00:00 [received]
PHST- 2023/11/25 00:00 [accepted]
PHST- 2024/02/10 14:43 [medline]
PHST- 2024/02/09 12:44 [pubmed]
PHST- 2024/02/09 10:14 [entrez]
PHST- 2024/01/24 00:00 [pmc-release]
AID - cells13030214 [pii]
AID - cells-13-00214 [pii]
AID - 10.3390/cells13030214 [doi]
PST - epublish
SO  - Cells. 2024 Jan 24;13(3):214. doi: 10.3390/cells13030214.