Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-induced hypertension

Am J Physiol Cell Physiol. 2016 Oct 1;311(4):C596-C606. doi: 10.1152/ajpcell.00088.2016. Epub 2016 Aug 3.


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-1β, IL-6, and TNF-α) 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 β-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-1β, IL-6, and TNF-α 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.

Keywords: homocysteine; inward vascular remodeling; mitochondria-mediated cell death; peripheral resistance; vascular inflammation.

MeSH terms

  • Animals
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Death / genetics
  • Cystathionine beta-Synthase / metabolism
  • Hyperhomocysteinemia / genetics*
  • Hyperhomocysteinemia / metabolism
  • Hypertension / genetics*
  • Hypertension / metabolism
  • Inflammation / genetics
  • Inflammation / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Toll-Like Receptor 4 / genetics*
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • bcl-2-Associated X Protein / metabolism


  • Interleukin-1beta
  • Interleukin-6
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • bcl-2-Associated X Protein
  • Caspase 3
  • Caspase 9
  • Cystathionine beta-Synthase