Our recent study demonstrated that HDAC4 protein specifically increases in mesenteric artery from spontaneous hypertensive rats (SHR) compared with Wistar Kyoto rats (WKY). Vascular inflammation is important for pathogenesis of hypertension. We examined whether HDAC4 affects vascular inflammatory responses and promotes hypertension. In vivo, blood pressure, reactive oxygen species (ROS) production, and VCAM-1 expression in isolated mesenteric artery were elevated in young SHR (7 wk old) compared with age-matched WKY, which were prevented by long-term treatment of SHR with an HDACs inhibitor, trichostatin A (TSA; 500 g·kg Ϫ1 ·day Ϫ1 for 3 wk). In isolated mesenteric artery, the increased angiotensin II-induced contraction in SHR was reversed by TSA. The endothelium-dependent relaxation induced by ACh in SHR was augmented by TSA. In cultured rat mesenteric arterial smooth muscle cells (SMCs), expression of HDAC4 mRNA and protein was increased by TNF-␣ (10 ng/ml). TSA (10 M, pretreatment for 30 min) inhibited VCAM-1 expression and NF-B phosphorylation induced by TNF (10 ng/ml, 24 h or 20 min) in SMCs. HDAC4 small interfering RNA inhibited TNF-induced monocyte adhesion, VCAM-1 expression, transcriptional activity of NF-B, and ROS production in SMCs. The present results demonstrated that proinflammatory effects of HDACs may mediate the further development of hypertension in SHR. It is also suggested in cultured vascular SMCs that TNF-induced HDAC4 mediates vascular inflammation likely via VCAM-1 induction through ROS-dependent NF-B activation. oxygen radicals; smooth muscle; contractile function CAM IS ASSOCIATED WITH A VARIETY of cell functions including inflammation, apoptosis, and muscular contraction. Recent evidence indicates that CaM-related proteins are responsible for cardiovascular diseases. In the previous study, we compared expression levels of six CaM-related proteins with almost unknown functions in vasculature [CaMKII␦, eukaryotic elongation factor 2 kinase (eEF2K; also known as CaMKIII), histone deacetylase (HDAC)4, HDAC5, death associated protein kinase (DAPK)3, and CaM serine kinase (CASK)] in aorta and mesenteric artery from spontaneous hypertensive rats (SHR) and Wistar Kyoto rats (WKY) (48). As a result, we for the first time demonstrated that expressions of eEF2K, HDAC4, and DAPK3 protein increased in SHR compared with WKY. However, it remained to be clarified how each CaM-related protein might affect vascular pathophysiology and control the development of hypertension.HDACs have been considered as transcriptional corepressors that catalyze histone deacetylation in diverse physiological systems (33, 42). Up to now, HDACs have been classified into four groups termed class I HDACs (HDAC1, 2, 3, and 8), class II HDACs (HDAC4, 5, 6, 7, 9, and 10), class III HDACs, and class IV HDAC (HDAC11). The class II HDACs are further divided into the class IIa (HDAC4, 5, 7, 9) and the class IIb (HDAC6 and 10) (26). A recent study clarified that the class I and IIa HDACs play critical roles in mediating cardiac h...

Blood chemerin concentration shows positive correlation not only with body mass index and serum triglyceride level but also with systolic blood pressure. While it seems likely that chemerin influences vascular smooth muscle cell (SMC) proliferation and migration, which are crucial to the development of hypertension, this remains to be clarified. In the present study, we investigated whether chemerin controls SMC proliferation and migration in vitro and also affects blood pressure in vivo. In vitro, chemerin significantly stimulated rat mesenteric arterial SMC proliferation and migration, as determined by a cell counting assay and Boyden chamber assay, respectively. The migratory effect of chemerin was confirmed in human aortic SMCs. Chemerin significantly increased ROS production in SMCs and phosphorylation of Akt (Ser(473)) and ERK, as measured by fluorescent staining and Western blot analysis, respectively. Various inhibitors (ROS inhibitor: N-acetyl-l-cysteine, phosphatidylinositol 3-kinase inhibitor: LY-294002, MAPKK inhibitor: PD-98059, NADPH oxidase inhibitor: gp91 ds-tat, and xanthine oxidase inhibitor: allopurinol) as well as chemokine-like receptor 1 small interfering RNA significantly inhibited chemerin-induced SMC proliferation and migration. Furthermore, chemerin-neutralizing antibody prevented carotid neointimal hyperplasia in the mouse ligation model. In vivo, chronic chemerin treatment (6 μg/kg, 6 wk) increased systolic blood pressure as well as phosphorylation of Akt and ERK in the mouse isolated aorta. In summary, we, for the first time, demonstrate that chemerin/chemokine-like receptor 1 stimulates SMC proliferation and migration via ROS-dependent phosphorylation of Akt/ERK, which may lead to vascular structural remodeling and an increase in systolic blood pressure.

INTRODUCTION Rotavirus A (RVA) is a major cause of gastroenteritis in infants and young children worldwide. In 2016, RVA caused 128,500 deaths in children under 5 years of age globally (1). Although most of these deaths occurred in developing countries, RVA imposes a huge burden even in developed countries, including Japan (2-4). Live attenuated RVA vaccines were introduced in Japan in 2011 (Rotarix ® , GlaxoSmithKline Biologicals, Rixensart, Belgium) and in 2012 (RotaTeq ® , Merck & Co., Inc., Kenilworth, NJ, USA), and while RVA vaccines have proven to be effective (5,6), the selective pressure of a vaccine may induce an epidemic strain shift (7-10). The RVA genome contains 11 gene segments of double-stranded RNA that encode six structural (VPs) and six nonstructural proteins (NSPs) (11). To classify RVAs, a specific genotype is assigned to each of the 11 genome segments, according to predefined nucleotide sequence identity cutoff values (12-14). The classification system denotes the VP7-VP4-VP6-VP1-VP2-VP3-NSP1-NSP2-NSP3-NSP4-NSP5 6 genes of an RVA strain as a descriptor Gx-P[x]-Ix-Rx-Cx-Mx-Ax-Nx-Tx-Ex-Hx (x indicating genotype number),

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We investigated whether cutaneous stimulus threshold (CST), as determined using a Neurometer, could be used for quantitative and differential nerve evaluation of reversible and irreversible nerve block following intrathecal lidocaine administration in rats. Rats with intrathecal catheters were randomly assigned to one of five groups (saline or 2, 5, 10, or 20% lidocaine). Prior to and 4 days after drug administration, CST was determined at 5, 250, and 2000 Hz. In the 2% lidocaine group, CST from end of lidocaine infusion to recovery from anesthesia was also monitored. Skin-clamp testing and gait observation were performed for comparison with CST findings. Behavioral examinations revealed persistent sensory or motor impairment lasting 4 days in groups receiving Ն5% lidocaine but not in the saline and 2% lidocaine groups. With 2% lidocaine, return to baseline CSTs at 5 and 250 Hz was delayed compared with thresholds at 2000 Hz. Although CSTs in the 5% group at 5 and 250 Hz increased significantly, thresholds at 2000 Hz did not differ from those in rats administered saline. CSTs with Ն10% lidocaine displayed no differences between frequencies. At each frequency, CSTs for rats with Ն5% lidocaine increased in a clearly concentration-dependent manner. These results suggest that CST testing enables evaluation of the different nerve functions for A␤, A␦, and C fibers in rats for lidocaine concentrations Յ5% and allows quantitative assessment of persistent neurological deficit induced by lidocaine in rats.

These results show that all four local anesthetics form molecular aggregations in the same manner as dodecyltrimethylammonium chloride, a common surfactant. At osmotic pressures insufficient to affect the membrane, local anesthetics caused membrane disruption at the same concentrations at which molecular aggregation occurred. This shows that disruption of the model membrane results from the detergent nature of local anesthetics. Nerve membrane solubilization by highly concentrated local anesthetics may cause irreversible neural injury.

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