{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:33:12Z","timestamp":1787243592297,"version":"build-2736575974"},"reference-count":67,"publisher":"American Physiological Society","issue":"4","funder":[{"name":"NIH","award":["HL-74185"],"award-info":[{"award-number":["HL-74185"]}]},{"name":"NIH","award":["HL-108621"],"award-info":[{"award-number":["HL-108621"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2016,10,1]]},"abstract":"<jats:p>\n                    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-1\u03b2, IL-6, and TNF-\u03b1) 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 \u03b2-synthase (CBS)-deficient (CBS\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ) mice with genetic mild HHcy, C3H\/HeJ (C3H) mice with TLR-4 mutation, and mice with combined genetic HHcy and TLR-4 mutation (CBS\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    \/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\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice. RI, PI, and wall-to-lumen ratio of the SMA in CBS\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    \/C3H mice were similar to the control group, and BP was significantly alleviated. TLR-4, IL-1\u03b2, IL-6, and TNF-\u03b1 expression were upregulated in the SMA of CBS\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice and reduced in the SMA of CBS\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    \/C3H mice. Molecules involved in the mitochondria-mediated cell death pathway (BAX, caspase-9, and caspase-3) were upregulated in CBS\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice and attenuated in CBS\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    \/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.\n                  <\/jats:p>","DOI":"10.1152\/ajpcell.00088.2016","type":"journal-article","created":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T22:59:18Z","timestamp":1470265158000},"page":"C596-C606","source":"Crossref","is-referenced-by-count":32,"title":["Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-induced hypertension"],"prefix":"10.1152","volume":"311","author":[{"given":"Anastasia","family":"Familtseva","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj","family":"Chaturvedi","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, University of Louisville, Louisville, 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