Plasma levels of IL-6 correlate with high blood pressure under many circumstances, and ANG II has been shown to stimulate IL-6 production from various cell types. This study tested the role of IL-6 in mediating the hypertension caused by high-dose ANG II and a high-salt diet. Male C57BL6 and IL-6 knockout (IL-6 KO) mice were implanted with biotelemetry devices and placed in metabolic cages to measure mean arterial pressure (MAP), heart rate (HR), sodium balance, and urinary albumin excretion. Baseline MAP during the control period averaged 114 +/- 1 and 109 +/- 1 mmHg for wild-type (WT) and IL-6 KO mice, respectively, and did not change significantly when the mice were placed on a high-salt diet (HS; 4% NaCl). ANG II (90 ng/min sc) caused a rapid increase in MAP in both groups, to 141 +/- 9 and 141 +/- 4 in WT and KO mice, respectively, on day 2. MAP plateaued at this level in KO mice (134 +/- 2 mmHg on day 14 of ANG II) but began to increase further in WT mice by day 4, reaching an average of 160 +/- 4 mmHg from days 10 to 14 of ANG II. Urinary albumin excretion on day 4 of ANG II was not different between groups (9.18 +/- 4.34 and 8.53 +/- 2.85 microg/2 days for WT and KO mice). By day 14, albumin excretion was nearly fourfold greater in WT mice, but MAP dropped rapidly back to control levels in both groups when the ANG II was stopped after 14 days. Thus the approximately 30 mmHg greater ANG II hypertension in the WT mice suggests that IL-6 contributes significantly to ANG II-salt hypertension. In addition, the early separation in MAP, the albumin excretion data, and the rapid, post-ANG II recovery of MAP suggest an IL-6-dependent mechanism that is independent of renal injury.

Abstract-Under normal conditions, contractile activity in vascular smooth muscle is initiated by either receptor activation (norepinephrine, angiotensin II, etc.) or by a stretch-activated mechanism. After this activation, several signaling pathways can initiate a Ca 2ϩ -calmodulin interaction to stimulate phosphorylation of the light chain of myosin. Ca 2ϩ sensitization of the contractile proteins is signaled by the RhoA/Rho-kinase pathway to inhibit the dephosphorylation of the light chain by myosin phosphatase thereby maintaining force generation. In opposition to force generation, NO is released from endothelial cells and causes vasodilation through inhibition of the RhoA/Rho-kinase signaling pathway. This brief review will highlight recent studies demonstrating a role for the RhoA/Rho-kinase signaling pathway in the increased vasoconstriction characteristic of hypertension. Key Words: vasculature Ⅲ signal transduction Ⅲ muscle, smooth Ⅲ nitric oxide Ⅲ vasoconstriction I ncreased peripheral vascular resistance causes elevated arterial pressure in hypertension. Arterial wall thickening, increased vasoconstriction, and reduced vasodilation contribute to this increased peripheral resistance. Multiple regulatory processes (neural, humoral, etc.) and complex cell signaling pathways modulate vascular smooth muscle cell (VSMC) contraction, relaxation, and growth. Under normal conditions, these regulatory processes maintain vessel wall integrity and do not contribute to pathological increases in blood pressure. Remodeling of the vasculature in hypertension involves rearrangement of cellular and extracellular components and has been reviewed extensively. [1][2][3][4][5][6] The present review highlights recent developments in the understanding of cellular and molecular mechanisms underlying increased vasoconstriction in hypertension with an emphasis on the RhoA/Rhokinase signaling pathway in vascular smooth muscle. Contractile MechanismVascular smooth muscle contraction is principally regulated by receptor and mechanical (stretch) activation of the contractile proteins. 7 Depolarization of the plasma membrane can also trigger contraction. For contraction to occur, myosin light chain (MLC) kinase must phosphorylate the light chain of myosin, enabling the cycling of myosin cross-bridges with actin. 7-9 Thus, contractile activity is determined primarily by the phosphorylation state of the light chain of myosin. 8,9 In VSMCs of some blood vessels, phosphorylation of the light chain of myosin is maintained at a low level in the absence of external stimuli (ie, no receptor or mechanical activation). This activity results in what is known as myogenic tone.Recent work suggests that 20-HETE may play a signaling role in the myogenic response of pig coronary arteries. Randriamboavonjy et al 10 observed that 20-HETE elicited contraction and phosphorylation of the light chain of myosin. Both of these activities were inhibited by Y-27632, a Rhokinase inhibitor (see below for description of signaling pathway). Ca 2؉ -Dependent Con...

The results indicate that IL-6 expression is essential for angiotensin II-induced increases in retinal VEGF expression, leukostasis, and vascular remodeling. The data suggest a critical role for IL-6 in mediating angiotensin II-induced retinal vascular inflammation and remodeling.

Abstract-This study tested the hypothesis that the inflammatory cytokine, interleukin-6, contributes to the hypertensive response to acute psychosocial stress, caused by switching male mice to a cage previously occupied by a different male mouse. Male C57BL6 (WT) and interleukin-6 (IL-6) knockout (KO) mice were implanted with biotelemetry devices to monitor mean arterial pressure, heart rate, and motor activity in the unrestrained state. Baseline mean arterial pressure was 98Ϯ1 and 103Ϯ1 for WT and IL-6 KO mice. Cage switch increased mean arterial pressure by 42Ϯ2 mm Hg in WT mice, but this was blunted significantly in KO mice (31Ϯ3 mm Hg peak increase). Area under the curve for the first 90 minutes also was significantly less. Heart rate and motor activity increased similarly, and there also were no differences in the increases in plasma renin activity or plasma norepinephrine concentration between WT and KO mice. Thus, the acute hypertensive response to psychosocial stress depends significantly on IL-6, and the effect appears to be specific for blood pressure rather than to a global impairment in the response to stress. However, because perfusion of the isolated mesenteric bed with phenylephrine and chronic infusion of angiotensin II caused similar responses in WT and IL-6 KO mice, it is clear that future studies are needed to determine to what extent the acute blood pressure effect of IL-6 is stress-specific.

BackgroundThough the precise cause(s) of Alzheimer’s disease (AD) remain unknown, there is strong evidence that decreased clearance of β-amyloid (Aβ) from the brain can contribute to the disease. Therapeutic strategies to promote natural Aβ clearance mechanisms, such as the protein apolipoprotein-E (APOE), hold promise for the treatment of AD. The amount of APOE in the brain is regulated by nuclear receptors including retinoid X receptors (RXRs). Drugs that activate RXRs, including bexarotene, can increase APOE and ABCA1 production, and have been shown to decrease the Aβ burden and improve cognition in mouse models of Aβ amyloidosis. Although recent bexarotene studies failed to replicate the rapid clearance of Aβ from brains, behavioral and cognitive effects of this compound remain controversial.FindingsIn efforts to clarify these behavioral findings, mutant APP/PS1 mice were acutely dosed with bexarotene. While ABCA1 was upregulated in mutant APP/PS1 mice treated with bexarotene, this drug failed to attenuate Aβ plaques or cognitive deficits in these mice.ConclusionsWe recommend rigorous preclinical study to evaluate the mechanism and utility of such a compound for AD therapy.