Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-induced hypertension

Area of Science:

• Vascular Biology
• Immunology
• Cardiovascular Disease

Background:

• Hyperhomocysteinemia (HHcy) is linked to hypertension, but underlying mechanisms remain unclear.
• Toll-like receptor 4 (TLR-4) activation promotes vascular inflammation, a key factor in hypertension pathogenesis.

Purpose of the Study:

• To investigate the hypothesis that HHcy induces hypertension via TLR-4 activation.
• To elucidate the role of TLR-4 in HHcy-induced vascular inflammation, apoptosis, and hypertension.

Main Methods:

• Utilized genetically modified mouse models: wild-type (WT), HHcy (CBS+/-), TLR-4 mutant (C3H), and combined HHcy/TLR-4 mutant (CBS+/-/C3H).
• Assessed vascular function using superior mesenteric artery (SMA) ultrasonography (wall-to-lumen ratio, resistive index [RI], pulsatility index [PI]).
• Measured blood pressure (BP) via tail cuff and quantified expression of TLR-4, inflammatory cytokines (IL-1β, IL-6, TNF-α), and apoptosis markers (BAX, caspase-9, caspase-3) in SMA tissue.

Main Results:

• CBS+/- mice exhibited elevated BP, increased SMA wall-to-lumen ratio, RI, and PI, alongside upregulated TLR-4, inflammatory cytokines, and apoptosis markers.
• CBS+/-/C3H mice showed normalized SMA parameters and BP, with reduced expression of TLR-4, inflammatory cytokines, and apoptosis markers compared to CBS+/- mice.
• TLR-4 mutation significantly attenuated HHcy-induced vascular inflammation and cell death.

Conclusions:

• HHcy promotes hypertension by activating TLR-4, leading to chronic vascular inflammation and mitochondria-dependent cell death.
• TLR-4 plays a critical role in mediating HHcy-induced vascular damage and hypertension.
• Targeting TLR-4 may represent a potential therapeutic strategy to suppress hypertension in HHcy patients.