Inhibition of TNF in the Brain Reverses Alterations in RAS Components and Attenuates Angiotensin II-Induced Hypertension

Abstract

Dysfunction of brain renin-angiotensin system (RAS) components is implicated in the development of hypertension. We previously showed that angiotensin (Ang) II-induced hypertension is mediated by increased production of proinflammatory cytokines (PIC), including tumor necrosis factor (TNF), in brain cardiovascular regulatory centers such as the paraventricular nucleus (PVN). Presently, we tested the hypothesis that central TNF blockade prevents dysregulation of brain RAS components and attenuates Ang II-induced hypertension. Male Sprague-Dawley rats were implanted with radio-telemetry transmitters to measure mean arterial pressure (MAP) and subjected to intracerebroventricular (ICV) infusion of etanercept (10 µg/kg/day) with/without concurrent subcutaneous 4-week Ang II (200 ng/kg/min) infusion. Chronic Ang II infusion resulted in a significant increase in MAP and cardiac hypertrophy, which was attenuated by inhibition of brain TNF with etanercept. Etanercept treatment also attenuated Ang II-induced increases in PIC and decreases in IL-10 expression in the PVN. Additionally, Ang II infusion increased expression of pro-hypertensive RAS components (ACE and AT1R), while decreasing anti-hypertensive RAS components (ACE2, Mas, and AT2 receptors), within the PVN. ICV etanercept treatment reversed these changes. Ang II-infusion was associated with increased oxidative stress as indicated by increased NAD(P)H oxidase activity and super oxide production in the PVN, which was prevented by inhibition of TNF. Moreover, brain targeted TNF blockade significantly reduced Ang II-induced NOX-2 and NOX-4 mRNA and protein expression in the PVN. These findings suggest that chronic TNF blockade in the brain protects rats against Ang II-dependent hypertension and cardiac hypertrophy by restoring the balance between pro- and anti-hypertensive RAS axes and inhibiting PIC and oxidative stress genes and proteins in the PVN.

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

“…Increased proinflammatory cytokines expression in autonomic control areas, as the PVN, has been identified as a major central molecular mechanism to decrease baroreflex function, to reduce HR variability, and to increase pressure variability and renal sympathetic nerve activity, thus contributing to the development/maintenance of hypertension (7,13,18,38,39). It was also shown that hypertensive rats exhibit elevated proinflammatory cytokines TNF-␣ and IL-6 expression in the PVN (2,31).…”

“…PVN was isolated from frozen brain sections using a Stoelting brain punch (Stoelting) and, then, the tissue was homogenized with RIPA lysis buffer, as previously described (2,7,18,39). The protein concentration was measured using a bicinchoninic acid (BCA) protein assay kit (Pierce).…”

“…In addition, it was demonstrated that acute microinjection of proinflammatory molecules into the PVN of normotensive rats causes elevation of both arterial pressure and renal sympathetic nerve activity (38). On the other hand, chronic inhibition of proinflammatory signaling in the brain decreased arterial pressure and renal sympathetic nerve activity, and reversed the deleterious cardiac remodeling in hypertensive rats (7,13,18,39). Therefore, brain inflammation emerges as a central factor that contributes to autonomic and cardiovascular abnormalities in hypertension.…”

Targeting Interleukin-1 beta to Suppress Sympathoexcitation in Hypothalamic Paraventricular Nucleus in Dahl Salt-Sensitive Hypertensive Rats

“…NOX-2 and NOX-4 mRNA expression was determined by real-time RT-PCR as previously described [18,23]. The primer sequences used were as follows: NOX-2 forward 5 0 -CTGCCAGTGTGTCGGAATCT-3 0 ; NOX-2 reverse 5 0 -TGTGAATGGCCGTGTGAAGT-3 0 ; NOX-4 forward 5 0 -GGATCACAGAAGGTCCCTAGC-3 0 ; NOX-4 reverse 5 0 -AGAAGTTCAGGGCGTTCACC-3 0 ; GAPDH forward 5 0 -AGACAGCCGCATCTTCTTGT-3 0 ; and GAPDH reverse 5 0 -CTTGCCGTGGGTAGAGTCAT-3 0 .…”

Perivascular Adipose Tissue, Vascular Reactivity and Hypertension

“…Therefore, there is the possibility that the loss of the anticontractile effect of PVAT in hypertension could be due to a release of TNF-α, which then exerts a procontractile effect by a mechanism involving generation of reactive oxygen species and angiotensin II [62,66]. The observations that treatment with TNF-α antagonist reduced angiotensin-induced hypertension [67,68] and that chronic blockade of angiotensin AT 1 receptor significantly reduced circulating levels of TNF-α [69] are consistent with the existence of cross-talk between angiotensin II and TNF-α (fig. 3).…”