Torcetrapib impairs endothelial function in hypertension

Area of Science:

• Pharmacology
• Cardiovascular Research
• Endothelial Biology

Background:

• Cholesterol ester transfer protein (CETP) inhibitor torcetrapib increased HDL but also all-cause mortality in the ILLUMINATE trial.
• Underlying mechanisms for torcetrapib's adverse effects remain unclear, necessitating investigation into potential off-target actions.

Purpose of the Study:

• To investigate the potential off-target effects of torcetrapib on endothelial function.
• To elucidate the mechanisms contributing to torcetrapib-associated mortality.

Main Methods:

• Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were treated with torcetrapib or placebo for 3 weeks.
• Vascular reactivity, nitric oxide (NO) release, reactive oxygen species (ROS) generation, and endothelin-1 (ET-1) levels were assessed.
• Effects of ET-1 receptor blockade with bosentan were evaluated.

Main Results:

• Torcetrapib impaired endothelium-dependent relaxations and reduced endothelial nitric oxide synthase (eNOS) mRNA and protein in SHRs.
• Torcetrapib decreased NO release, increased ROS generation, and elevated vascular ET-1 levels.
• Bosentan treatment normalized endothelial function in torcetrapib-treated SHRs.

Conclusions:

• Torcetrapib induces sustained endothelial dysfunction, reduced NO bioavailability, and increased oxidative stress and ET-1 production.
• These detrimental effects are preventable with ET(A/B)-receptor blockade.
• Novel CETP inhibitors require thorough evaluation for similar off-target effects before clinical use in high-risk populations.