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Vascular smooth muscle cell (VSMC) proliferation and migration and vascular endothelial cell (VEC) dysfunction are closely associated with the development of atherosclerosis. We previously demonstrated that protein tyrosine phosphatase [epsilon] M (PTP[epsilon]M) promotes VEC survival and migration. The present study investigates the biological functions of PTP[epsilon]M in VSMCs and determines whether PTP[epsilon]M is implicated in diabetes-accelerated atherosclerosis. We overexpressed wild-type and inactive PTP[epsilon]M and an small interfering RNA (siRNA) of PTP[epsilon]M by using an adenovirus vector to investigate the effects of PTP[epsilon]M upon platelet-derived growth factor (PDGF)- and high glucose (HG)-induced responses of rat VSMCs in vitro. We found that PTP[epsilon]M decreased PDGF-induced DNA synthesis and migration by reducing the phosphorylation level of the PDGF [beta]-receptor (PDGFR[beta]) with subsequently suppressed [H.sub.2][O.sub.2] generation. The HG content in the medium generated [H.sub.2][O.sub.2], upregulated PDGFR[beta] expression and its tyrosine-phosphorylation, and elevated NADPH oxidase 1 (Nox1) expression even without exogenous PDGF, all of which were downregulated by PTP[epsilon]M. The PDGFR inhibitor AG1296 also blocked HG-induced Nox1 expression and [H.sub.2][O.sub.2] production. Moreover, HG suppressed PTP[epsilon]M expression itself, which was blocked by the antioxidant N-acetyl-L-cysteine. The effects of PTP[epsilon]M siRNA were the opposite of those of wild-type PTP[epsilon]M. Therefore, PTP[epsilon]M negatively regulates PDGFR[beta]-mediated signaling pathways that are crucial for the pathogenesis of atherosclerosis, and PTP[epsilon]M may be involved in diabetes-accelerated atherosclerosis. platelet-derived growth factor; protein tyrosine phosphatase [epsilon] M; reactive oxygen species; diabetes; atherosclerosis doi: 10.1152/ajpcell.00536.2009.

Patients with chronic renal failure are at greater risk of developing atherosclerosis than healthy individuals, and recent data suggest that the putative uremic toxin indoxyl sulfate (IS) promotes the pathogenesis of atherosclerosis. The present study examined the effects of IS on vascular smooth muscle cells (VSMCs) with respect to reactive oxygen species (ROS), platelet-derived growth factor (PDGF) receptors, and mitogen-activated protein kinases (MAPKs). IS induced the migration and proliferation of VSMCs and synergistically enhanced their PDGF-induced migration as well as proliferation. The effects of PDGF were promoted after a 24-h incubation with IS despite the absence of IS during PDGF stimulation. Intracellular ROS levels were increased in the presence of IS, and PDGF-dependent ROS production was augmented by a prior 24-h incubation with IS even in the absence of IS during PDGF stimulation. These data suggest that IS increases the sensitivity of VSMCs to PDGF. IS also phosphorylated PDGF-[beta]-receptors and upregulated PDGF-[beta] receptor but not a-receptor protein expression in the absence of exogenous PDGF. The NADPH oxidase inhibitor diphenylene iodonium blocked IS-dependent increase in receptor expression. Administration of IS to nephrectomized rats also elevated receptor protein expression in arterial VSMCs. Inhibitors of NADPH oxidase, PDGF-[beta] receptors, extracellular-regulated protein kinase (ERK), and p38 MAPK all inhibited IS-induced VSMCs migration and proliferation. Taken together, these findings indicate that IS induces the migration as well as proliferation of VSMCs through PDGF-[beta] receptors and that ROS generation is critically involved in this process, which promotes the development of atherosclerosis. uremic toxin; chronic renal failure; atherosclerosis; reactive oxygen species; platelet-derive growth factor-[beta]

c-Jun N[H.sub.2]-terminal kinase (JNK) is highly expressed in skeletal muscle and is robustly activated in response to muscle contraction. Little is known about the biological functions of JNK signaling in terminally differentiated muscle cells, although this protein has been proposed to regulate insulin-stimulated glycogen synthase activity in mouse skeletal muscle. To determine whether JNK signaling regulates contraction-stimulated glycogen synthase activation, we applied an electroporation technique to induce JNK overexpression (O/E) in mouse skeletal muscle. Ten days after electroporation, in situ muscle contraction increased JNK activity 2.6-fold in control muscles and 15-fold in the JNK O/E muscles. Despite the enormous activation of JNK activity in JNK O/E muscles, contraction resulted in similar increases in glycogen synthase activity in control and JNK O/E muscles. Consistent with these findings, basal and contraction-induced glycogen synthase activity was normal in muscles of both JNK1- and JNK2-deficient mice. JNK overexpression in muscle resulted in significant alterations in the basal phosphorylation state of several signaling proteins, such as extracellular signal-regulated kinase 1/2, p90 S6 kinase, glycogen synthase kinase 3, protein kinase B/Akt, and p70 S6 kinase, in the absence of changes in the expression of these proteins. These data suggest that JNK signaling regulates the phosphorylation state of several kinases in skeletal muscle. JNK activation is unlikely to be the major mechanism by which contractile activity increases glycogen synthase activity in skeletal muscle. electroporation; gene delivery; muscle contraction; exercise

Iemitsu, Motoyuki, Takashi Miyauchi, Seiji Maeda, Satoshi Sakai, Tsutomu Kobayashi, Nobuharu Fujii, Hitoshi Miyazaki, Mitsuo Matsuda, and Iwao Yamaguchi. Physiological and pathological cardiac hypertrophy induce different molecular phenotypes in the rat. Am J Physiol Regulatory Integrative Comp Physiol 281: R2029--R2036, 2001.--Pressure overload, such as hypertension, to the heart causes pathological cardiac hypertrophy, whereas chronic exercise causes physiological cardiac hypertrophy, which is defined as athletic heart. There are differences in cardiac properties between these two types of hypertrophy. We investigated whether mRNA expression of various cardiovascular regulating factors differs in rat hearts that are physiologically and pathologically hypertrophied, because we hypothesized that these two types of cardiac hypertrophy induce different molecular phenotypes. We used the spontaneously hypertensive rat (SHR group; 19 wk old) as a model of pathological hypertrophy and swim-trained rats (trained group; 19 wk old, swim training for 15 wk) as a model of physiological hypertrophy. We also used sedentary Wistar-Kyoto rats as the control group (19 wk old). Left ventricular mass index for body weight was significantly higher in SHR and trained groups than in the control group. Expression of brain natriuretic peptide, angiotensin-converting enzyme, and endothelin-1 mRNA in the heart was significantly higher in the SHR group than in control and trained groups. Expression of adrenomedullin mRNA in the heart was significantly lower in the trained group than in control and SHR groups. Expression of [[beta].sub.1]-adrenergic receptor mRNA in the heart was significantly higher in SHR and trained groups than in the control group. Expression of [[beta].sub.1]-adrenergic receptor kinase mRNA, which inhibits [[beta].sub.1]-adrenergic receptor activity, in the heart was markedly higher in the SHR group than in control and trained groups. We demonstrated for the first time that the manner of mRNA expression of various cardiovascular regulating factors in the heart differs between physiological and pathological cardiac hypertrophy. cardiovascular regulating factor; athletic heart; spontaneously hypertensive rat; swim training; hypertension Recieved 23 April 2001; accepted in final form 27 July 2001

A study was conducted to analyze the space and time association between type 2 angiotensin II receptors (AT2) expression and follicle atresia in vivo. The influence of AT2 on follicle-stimulating hormone (FSH) actions in vitro was also examined. Immature female Wistar-Imamichi rats were utilized to carry out the study. Results indicated that AT2 influences the progression of follicle atresia through granulosa cell apoptosis by inhibiting FSH.

Research was conducted to determine the effect of physical training on the beta-adrenergic (beta-AR) number in human lymphocytes by examining it as a function of aerobic capacity evaluated by maximal oxygen consumption and oxygen consumption level at ventilatory threshold. The number of beta-AR in the cell surface and intracellular compartment in intact lymphocytes was examined by calculating the lipophilic radioligand binding. Results indicate that there is an inverse correlation between the number of beta-AR in lymphocytes and aerobic capacity.