Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-induced hypertension

作者：Familtseva Anastasia; Chaturvedi Pankaj; Kalani Anuradha; Jeremic Nevena; Metreveli Naira; Kunkel George H; Tyagi Suresh C

来源：American Journal of Physiology - Cell Physiology, 2016, 311(4): C596-C606.

DOI：10.1152/ajpcell.00088.2016

• homocysteine
• vascular inflammation
• mitochondria-mediated cell death
• peripheral resistance
• inward vascular remodeling

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 beta, 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-tolumen 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-1 beta, 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.

• 出版日期2016-10-1