title: Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-induced hypertension.
abstract: 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.
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Familtseva
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chaturvedi
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kalani
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Nevena
authors.initials: N
authors.lastname: Jeremic
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Naira
authors.initials: N
authors.lastname: Metreveli
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: George H
authors.initials: GH
authors.lastname: Kunkel
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky s0tyag01@Louisville.edu.
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000235:genetics* / Q000378:metabolism; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D053453:Caspase 9; D003541:Cystathionine beta-Synthase
keywords: homocysteine; inward vascular remodeling; mitochondria-mediated cell death; peripheral resistance; vascular inflammation