Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-induced 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.
Source: AJP: Cell Physiology - Category: Cytology Authors: Tags: ARTICLES Source Type: research