Abstract-Vascular smooth muscle cell (VSMC) proliferation is a critical event in the development and progression of vascular diseases, including atherosclerosis. We investigated whether the activation of adenosine monophosphate-activated protein kinase (AMPK) could suppress VSMC proliferation and inhibit cell cycle progression. Treatment of human aortic smooth muscle cells (HASMCs) or isolated rabbit aortas with the AMPK activator 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) induced phosphorylation of AMPK and acetyl Co-A carboxylase. AICAR significantly inhibited HASMC proliferation induced by both platelet-derived growth factor-BB (PDGF-BB) and fetal calf serum (FCS). Treatment with AICAR inhibited the phosphorylation of retinoblastoma gene product (Rb) induced by PDGF-BB or FCS, and increased the expression of cyclin-dependent kinase inhibitor p21 CIP but not that of p27 KIP . Pharmacological inhibition of AMPK or overexpression of dominant negative-AMPK inhibited both the suppressive effect of AICAR on cell proliferation and the phosphorylation of Rb, suggesting that the effect of AICAR is mediated through the activation of AMPK. Cell cycle analysis in HASMCs showed that AICAR significantly increased cell population in G0/G1-phase and reduced that in S-and G2/M-phase, suggesting AICAR induced cell cycle arrest. AICAR increased both p53 protein and Ser-15 phosphorylated p53 in HASMCs, which were blocked by inhibition of AMPK. In isolated rabbit aortas, AICAR also increased Ser-15 phosphorylation and protein expression of p53 and inhibited Rb phosphorylation induced by FCS. These data suggest for the first time that AMPK suppresses VSMC proliferation via cell cycle regulation by p53 upregulation. Therefore, AMPK activation in VSMCs may be a therapoietic target for the prevention of vascular diseases.

Interferon-y may play an important role in the immune response and in inflammatory diseases, including chronic active hepatitis. To understand the role of interferon-y in the regulation of inflammation and to establish a mouse model of chronic active hepatitis, we produced transgenic mice in which the mouse interferon-y gene was regulated by a liver-specific promoter, the serum amyloid P component gene promoter. Four transgenic mouse lines were generated, and two of these lines expressed mRNA of interferon-y in the liver. Levels of serum transaminases increased gradually as a function of age and were significantly higher than those of interferon--negative littermates after 4 weeks after birth. One transgenic mouse line showed a histology of chronic active hepatitis similar to that found in human patients, although cirrhotic changes such as fibrosis were scarce. Thus, the liver-specific production of interferon-y is sufficient to induce chronic inflammatory disease and this mouse is a transgenic model of chronic active hepatitis.Chronic hepatic diseases, such as chronic active hepatitis and liver cirrhosis, are public health problems of worldwide importance and are major causes of mortality in certain areas of the world. Clinical and epidemiological studies (1-4) have clearly shown the importance of hepatitis B and C viruses (HBV, HCV) in chronic active hepatitis as well as hepatocellular carcinoma (HCC). Furthermore, studies ofpathology revealed that HCC arises in a cirrhotic liver and that chronic hepatitis is prerequisite for the development of HCC. The mechanisms responsible for HBV-or HCV-induced hepatocellular injury are not well understood. However, it is generally accepted that HBV is not directly cytopathic and that liver cell necrosis is dependent upon the host's immune response, directed at viral determinants on the hepatocyte membrane (5, 6). This immune response is mainly mediated by cytotoxic T lymphocytes (7).Several transgenic models of hepatic disease have been described. Chisari et al. (8) (10) showed that transgenic mice expressing the albumin-plasminogen activator gene develop progressive degenerative change in the liver due to accumulation ofRER-bounded multivesicular bodies. However, the principal lesion in these models appears to involve the hepatocyte secretory pathway and thus is different from that found in human patients.A model of acute hepatitis can be produced by administration of chemicals. However, remaining hepatocytes are induced to proliferate until the liver regains its original weight. Shull et al. (11) produced transforming growth factor (TGF)-,81-deficient mice. These mice developed an inflammatory liver disease similar to that found in HBV infection. However, about 20 days after birth these mice died due to a wasting syndrome. Mori et al. (12) demonstrated that liver changes histologically mimicking human hepatitis were produced in the mouse liver after repeated immunization with syngeneic crude liver proteins. However, it is not known whether hepatitis continues l...

Background: Recent cDNA cloning of two homologous proteasome activators, PA28a and PA28b, indicated the presence of a structurally related third protein, Ki antigen, but a functional relationship between Ki antigen and the two PA28 proteins is unknown. Accumulating evidence has implicated an important role for PA28 in the major histocompatibility complex (MHC) class I-restricted antigen processing pathway. Recently, an immunomodulatory cytokine g-interferon (g-IFN) was found to increase greatly the messages for PA28a and PA28b, but not Ki antigen, in human cells.

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare disorder and an unusual cause of Cushing s syndrome, of which familial transmission has rarely been reported. In this study, a mother and her son, the former affected with definite AIMAH and the latter with possible AIMAH, are described. Although the mother manifested overt Cushing s syndrome, her son remained with no stigmata of Cushing s syndrome except for bilateral adrenal tumor and mild hypertension, and a full suppression of plasma cortisol by lowdose dexamethasone was observed in him. Recently, aberrant expression of adrenal receptors for various ligands has been noted in AIMAH patients. In our cases, provocation tests in vivo suggested that AVP and catecholamines promoted cortisol production through V1a and/or V1b receptors and via beta-adrenergic receptor, respectively. Reverse transcriptional-PCR analysis of the operated adrenal tissues of mother revealed the abnormal expression of mRNA of receptors for V1b, V2, and LH/hCG, none of which was observed in a normal control. Inherited AIMAH is very rare, and the son might be at the earliest developmental stage of AIMAH among the cases reported so far. An intervention could be tried to prevent the development of overt Cushing s syndrome by suppression of the possible endogenous ligands or by blockade of the receptors that may be aberrantly expressed in his adrenal glands.