PMID- 27488663
OWN - NLM
STAT- MEDLINE
DCOM- 20170606
LR  - 20200930
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 311
IP  - 4
DP  - 2016 Oct 1
TI  - Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-induced 
      hypertension.
PG  - C596-C606
LID - 10.1152/ajpcell.00088.2016 [doi]
AB  - Hyperhomocysteinemia (HHcy) has been observed to promote hypertension, but the 
      mechanisms are unclear. Toll-like receptor 4 (TLR-4) is a cellular membrane 
      protein that is ubiquitously expressed in all cell types of the vasculature. 
      TLR-4 activation has been known to promote inflammation that has been associated 
      with the pathogenesis of hypertension. In this study we hypothesize that HHcy 
      induces hypertension by TLR-4 activation, which promotes inflammatory cytokine 
      (IL-1beta, IL-6, and TNF-alpha) upregulation and initiation of mitochondria-dependent 
      apoptosis, leading to cell death and chronic vascular inflammation. To test this 
      hypothesis, we used C57BL/6J (WT) mice, cystathionine beta-synthase (CBS)-deficient 
      (CBS(+/-)) mice with genetic mild HHcy, C3H/HeJ (C3H) mice with TLR-4 mutation, 
      and mice with combined genetic HHcy and TLR-4 mutation (CBS(+/-)/C3H). 
      Ultrasonography of the superior mesenteric artery (SMA) detected an increase in 
      wall-to-lumen ratio, resistive index (RI), and pulsatility index (PI). Tail cuff 
      blood pressure (BP) measurement revealed elevated BP in CBS(+/-) mice. RI, PI, 
      and wall-to-lumen ratio of the SMA in CBS(+/-)/C3H mice were similar to the 
      control group, and BP was significantly alleviated. TLR-4, IL-1beta, IL-6, and TNF-alpha 
      expression were upregulated in the SMA of CBS(+/-) mice and reduced in the SMA of 
      CBS(+/-)/C3H mice. Molecules involved in the mitochondria-mediated cell death 
      pathway (BAX, caspase-9, and caspase-3) were upregulated in CBS(+/-) mice and 
      attenuated in CBS(+/-)/C3H mice. We conclude that HHcy promotes TLR-4-driven 
      chronic vascular inflammation and mitochondria-mediated cell death, inducing 
      hypertension. TLR-4 mutation attenuates vascular inflammation and cell death, 
      which suppress hypertension.
CI  - Copyright (c) 2016 the American Physiological Society.
FAU - Familtseva, Anastasia
AU  - Familtseva A
AD  - Department of Physiology, School of Medicine, University of Louisville, 
      Louisville, Kentucky.
FAU - Chaturvedi, Pankaj
AU  - Chaturvedi P
AD  - Department of Physiology, School of Medicine, University of Louisville, 
      Louisville, Kentucky.
FAU - Kalani, Anuradha
AU  - Kalani A
AD  - Department of Physiology, School of Medicine, University of Louisville, 
      Louisville, Kentucky.
FAU - Jeremic, Nevena
AU  - Jeremic N
AD  - Department of Physiology, School of Medicine, University of Louisville, 
      Louisville, Kentucky.
FAU - Metreveli, Naira
AU  - Metreveli N
AD  - Department of Physiology, School of Medicine, University of Louisville, 
      Louisville, Kentucky.
FAU - Kunkel, George H
AU  - Kunkel GH
AD  - Department of Physiology, School of Medicine, University of Louisville, 
      Louisville, Kentucky.
FAU - Tyagi, Suresh C
AU  - Tyagi SC
AD  - Department of Physiology, School of Medicine, University of Louisville, 
      Louisville, Kentucky s0tyag01@Louisville.edu.
LA  - eng
GR  - F31 HL132527/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20160803
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Interleukin-1beta)
RN  - 0 (Interleukin-6)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (bcl-2-Associated X Protein)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 9)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
SB  - IM
MH  - Animals
MH  - Caspase 3/metabolism
MH  - Caspase 9/metabolism
MH  - Cell Death/genetics
MH  - Cystathionine beta-Synthase/metabolism
MH  - Hyperhomocysteinemia/*genetics/metabolism
MH  - Hypertension/*genetics/metabolism
MH  - Inflammation/genetics/metabolism
MH  - Interleukin-1beta/metabolism
MH  - Interleukin-6/metabolism
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Mice, Inbred C57BL
MH  - Mitochondria/genetics/metabolism
MH  - Toll-Like Receptor 4/*genetics/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - bcl-2-Associated X Protein/metabolism
PMC - PMC5129755
OTO - NOTNLM
OT  - homocysteine
OT  - inward vascular remodeling
OT  - mitochondria-mediated cell death
OT  - peripheral resistance
OT  - vascular inflammation
EDAT- 2016/08/05 06:00
MHDA- 2017/06/07 06:00
PMCR- 2017/10/01
CRDT- 2016/08/05 06:00
PHST- 2016/03/30 00:00 [received]
PHST- 2016/08/01 00:00 [accepted]
PHST- 2016/08/05 06:00 [pubmed]
PHST- 2017/06/07 06:00 [medline]
PHST- 2016/08/05 06:00 [entrez]
PHST- 2017/10/01 00:00 [pmc-release]
AID - ajpcell.00088.2016 [pii]
AID - C-00088-2016 [pii]
AID - 10.1152/ajpcell.00088.2016 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2016 Oct 1;311(4):C596-C606. doi: 
      10.1152/ajpcell.00088.2016. Epub 2016 Aug 3.