Central blockade of TLR4 improves cardiac function and attenuates pro-inflammatory cytokines and oxidative stress in hypertensive rats

Role of pro‐inflammatory cytokines (PICs) and oxidative stress within the paraventricular nucleus (PVN) in the pathogenesis of hypertension (HTN) is well established. Although role of toll‐like receptor 4 (TLR4) in various cardiovascular diseases is becoming evident, role of brain TLR4 in the pathogenesis of HTN has never been explored. We hypothesized that TLR4 upregulation within the PVN contributes to the development of HTN. Male SD rats were infused with Angiotensin II (AngII) (200 ng/kg/min) or vehicle by subcutaneous miniosmotic pumps; a subgroup of rats were given intracerebroventricular infusion of Viral Inhibitory Peptide (VIPER, a specific TLR4 blocker) or control peptide for 14 days. Mean arterial pressure (MAP) and cardiac function were evaluated by radio‐telemetry and echocardiography, respectively. PVN and heart tissues were analyzed by RT‐PCR and western blot. TLR4 expression was dramatically upregulated within the PVN of hypertensive rats. VIPER infusion attenuated MAP and improved cardiac function in hypertensive rats. Interestingly, VIPER infusion prevented the increase in PICs (TNF‐α and IL‐1β) and reduced oxidative stress markers (gp91phox and iNOS) in hypertensive rats. These results suggest that the brain TLR4 plays an important role in hypertensive response by modulating PICs and oxidative stress and that the central blockade of TLR4 exerts beneficial effects in HTN. Funding: LSU