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PubMed2001

Mutated p21/WAF/CIP transgene overexpression reduces smooth muscle cell proliferation, macrophage deposition, oxidation-sensitive mechanisms, and restenosis in hypercholesterolemic apolipoprotein E knockout mice.

We have investigated whether by introducing a mutated p21 cyclin-dependent kinase inhibitor through a standard type 5 adenovirus (Ad), it would be possible to interfere with restenosis in hypercholesterolemic apolipoprotein E knockout mice. Restenosis is a clinically relevant, undesired effect of percutaneous transluminal coronary angioplasty (PTCA). A critical event underlying restenosis is smooth muscle cell (SMC) proliferation leading to neointimal formation and vessel reocclusion. Recent data demonstrated that it is possible to reduce restenosis by introducing various genes blocking the cell cycle through Ad vectors. Nonetheless, most experiments were conducted in the healthy carotid artery of rat, which is far from the condition of human disease. Therefore, we investigated whether antiproliferative or proapoptotic genes affect restenosis in a model of atherosclerosis closer to clinical settings. Ad-mutated(m)-p21WAF/CIP1 transgene overexpression induces a significant reduction of restenosis in hypercholesterolemic apolipoprotein E knockout mice subjected to injury of common carotid artery. This was associated with reduced SMC density and proliferation, macrophage deposition, and oxidation-sensitive mechanisms. Treatment with p21/WAF also enhanced TUNEL positivity of arterial cells. We show that in an experimental model of atherosclerosis, braking the cell proliferation through increased vascular apoptosis and reduced oxidation-sensitive signal transduction and macrophage accumulation can significantly ameliorate the deleterious effects of vascular injuries similar to those that occur during PTCA and related procedures.

Adenoviridae↗

PubMed2006

Chronic liver disease is triggered by taurine transporter knockout in the mouse.

Taurine is an abundant organic osmolyte with antioxidant and immunomodulatory properties. Its role in the pathogenesis of chronic liver disease is unknown. The liver phenotype was studied in taurine transporter knockout (taut-/-) mice. Hepatic taurine levels were ~21, 15 and 6 mumol/g liver wet weight in adult wild-type, heterozygous (taut+/-) and homozygous (taut-/-) mice, respectively. Immunoelectronmicroscopy revealed an almost complete depletion of taurine in Kupffer and sinusoidal endothelial cells, but not in parenchymal cells of (taut-/-) mice. Compared with wild-type mice, (taut-/-) and (taut+/-) mice developed moderate unspecific hepatitis and liver fibrosis with increased frequency of neoplastic lesions beyond 1 year of age. Liver disease in (taut-/-) mice was characterized by hepatocyte apoptosis, activation of the CD95 system, elevated plasma TNF-alpha levels, hepatic stellate cell and oval cell proliferation, and severe mitochondrial abnormalities in liver parenchymal cells. Mitochondrial dysfunction was suggested by a significantly lower respiratory control ratio in isolated mitochondria from (taut-/-) mice. Taut knockout had no effect on taurine-conjugated bile acids in bile; however, the relative amount of cholate-conjugates acid was decreased at the expense of 7-keto-cholate-conjugates. In conclusion, taurine deficiency due to defective taurine transport triggers chronic liver disease, which may involve mitochondrial dysfunction.

Animals↗

PubMed2001

Transgenic and gene "knockout" models in alcohol research.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Paula L. Hoffman and Takeshi Yagi. The presentations were (1) cAMP signaling in ethanol sensitivity and tolerance, by Boris Tabakoff; (2) Synaptic signaling pathways of Fyn-tyrosine kinase, by Takeshi Yagi; (3) Ethanol drinking and sensitization in dopaminergic and serotonergic receptor knockouts, by Tamara J. Phillips; (4) ICAM-1 is involved in early alcohol-induced liver injury in the mouse given enteral alcohol, by Hiroshi Kono; and (5) Strategies for targeted and regulated knockouts, by Robert O. Messing and Doo-Sup Choi.

Adenylyl Cyclases↗

PubMed2003

Reduced programmed cell death in brains of serotonin transporter knockout mice.

Serotonin (5-HT) is known to reduce apoptosis and in rodent models of brain ischemia. Modulation of programmed cell death during neural development was assessed in early postnatal brains of serotonin transporter (5-HTT) knockout mice, characterized by elevated extracellular 5-HT levels. The number of apoptotic cells visualized at postnatal day-1 (P1) by ISEL+ or TUNEL staining was significantly reduced in the striatum, thalamus/hypothalamus, cerebral cortex and hippocampus of 5-HTT knockout mice, compared to wild type and heterozygote mice, with differences displaying an increasing fronto-caudal gradient and regional specificity. These findings underscore 5-HT roles in the regulation of programmed cell death during brain development, and spur interest into pharmacological interventions aimed at relieving pathological apoptosis by potentiating serotoninergic neurotransmission.

Animals↗

PubMed2003

Olfactory neurons in bax knockout mice are protected from bulbectomy-induced apoptosis.

Surgical ablation of the olfactory bulb (bulbectomy) triggers a massive wave of apoptosis in mature olfactory sensory neurons within the olfactory epithelium. The aim of the current study was to determine if this process is dependent on expression of the pro-apoptotic protein Bax. Immunohistochemical detection of caspase-3 activation and olfactory epithelial thickness was used to demonstrate and quantify neuronal apoptosis in bax knockout and wild type mice, following bulbectomy. Caspase-3 activation and epithelial thinning were both reduced in the bax knockout mouse compared to the wild type mouse, at least up to 9 days post-bulbectomy, indicating that apoptosis was inhibited not just delayed. This study demonstrates that Bax plays a major role in olfactory neuron apoptosis following surgical deafferentation.

Animals↗

PubMed2004

Partial protection against dextran sodium sulphate induced colitis in histamine-deficient, histidine decarboxylase knockout mice.

OBJECTIVES: Chemically induced mucosal inflammation in animal models is a suitable tool for studying factors in the pathogenesis of inflammatory bowel disease. The aim of this study was to determine whether absence of histamine has an effect on the development of experimental colitis. METHODS: Histamine-deficient, histidine decarboxylase (HDC) knockout Balb/c mice and genetically identical control animals with intact HDC were studied. Colitis was induced by the administration of 2% dextran sodium sulphate in drinking water. Mice were killed after 5 days and disease activity assessed by clinical, histologic, and immunohistologic parameters. Bacterial components of stool were examined. RESULTS: Clinical disease activity was higher in the mice with intact HDC (disease activity index, 2.21) than in the histamine-deficient knock-out mice (1.88). Histologic findings were similar in the two groups. On day 5, the inflammation score of the HDC sufficient group was 5.25 (+/-1.055) and the crypt score was 5.00 (+/-1.128). The scores in the HDC knock-out group were 4.667 (+/- 0.707) and 4.667 (+/- 0.86), respectively. There was a significant difference in the number of interleukin (IL-10)-producing lymphocytes in colon mucosa. Large numbers of IL-10-positive lymphocytes were observed in wild type mice both those with DSS induced colitis and untreated controls. Only sporadic IL-10 positivity was found in histamine-deficient mice. Significant differences were found in the composition of the fecal bacterial flora between the two groups. CONCLUSION: The reduced number of IL-10-positive lymphocytes in the intestinal mucosa of histamine-deficient, histidine decarboxylase knockout mice and the altered fecal bacterial flora in these animals suggest that histamine may play a role in the pathophysiology of inflammation in the colon of normal animals by upregulating local IL-10 production and stimulating a local shift to Th2 response.

Animals↗

PubMed1998

Systemic and renal response to salt loading in endothelin-1 knockout mice.

Endothelin-1 (ET-1) knockout mice demonstrate elevated blood pressure, which may be associated with disturbance in central cardiorespiratory regulation. In this study we examined responses to salt loading in ET-1 knockout mice to investigate whether ET-1 is involved in the pathophysiology of salt-sensitive hypertension. Male Edn1+/- heterozygous mice and their wild-type littermates were fed either a high NaCl (8%) or a normal (0.2%) diet for 4 weeks. Systemic blood pressure and tissue ET-1 levels were measured as well as several parameters relating to sodium handling and volume homeostasis. On normal diet, renal ET-1 levels of Edn1+/- mice were about 50% of those of wild-type mice. A high-salt diet caused a significant decrease in renal ET-1 levels by about 50% in both groups. Urine volume, urinary sodium excretion, and FENa in mice on the 8% NaCl diet were significantly higher than those in mice on the 0.2% NaCl diet, whereas there were no differences in circulating plasma volume, serum electrocytes, and creatinine clearance. These responses were similar in Edn1+/- and wild-type mice. Although systemic blood pressure was significantly higher in Edn1+/- mice than in the wild-type, the effect of salt loading on blood pressure was not significant in either Edn1+/- or wild-type mice. We conclude that changes in ET-1 production within a physiologic range do not affect salt sensitivity, although renal ET-1 content is decreased by salt loading.

Animals↗

PubMed1998

Neurotrophin 3, not brain-derived neurotrophic factor or neurotrophin 4, knockout mice have delay in vestibular compensation after unilateral labyrinthectomy.

On the basis that neurotrophins (NTs) affect neuronal synaptic plasticity, are expressed in various cell types of the vestibular system, and exert a trophic influence on statoacoustic neurons, the authors hypothesized a role for NTs in vestibular compensation. To test this hypothesis, they performed unilateral surgical labyrinthectomy in 11 heterozygous (+/-) neurotrophin 3 (NT3) and brain-derived neurotrophic factor (BDNF) knockout mice and in two neurotrophin 4 (NT4) homozygous (-/-) knockout mice, each with a control (+/+) sibling, for a total of 26 mice. Four BDNF(+/-) and four NT3(+/-) mice with their (+/+) controls each were allowed to recover in a normal lighted room for 3, 7, 14, and 30 days following labyrinthectomy. Two BDNF(+/-) and two NT4(-/-) mice with controls were kept in total darkness for 1- and 16-day survival periods. One NT3(+/-) mouse without a control (which died in surgery) was sacrificed after 16 days in darkness. The behavior of all mice was videorecorded to monitor their recovery. Compared with normal (+/+) littermate controls, NT3(+/-) mice demonstrated a delay in compensation (8 to 10 days) in light surround, whereas NT4(-/-) mice showed only a minor delay in dark surround. Despite a 40% lower vestibular ganglion cell population in BDNF(+/-) mice compared with (+/+) controls, BDNF(+/-) mice did not reveal a detectable delay in recovery following labyrinthectomy. These findings suggest that a 50% loss of NT3 protein significantly affects vestibular recovery in adult mice. Perhaps variations in achieving vestibular compensation in humans may be partly secondary to genetically different NT3 levels in vestibular pathways.

Animals↗

PubMed1999

The role of CD8 and CD4 T cells in intestinal allograft rejection: a comparison of monoclonal antibody-treated and knockout mice.

BACKGROUND: The relative contribution of CD8 and CD4 T cells to allograft rejection remains an unresolved issue. Experimental results suggest that the relative importance of these T-cell subsets may vary depending on the model used and the organ studied. We have previously shown that treatment of murine recipients of intestinal allografts with a depleting anti-CD8 or a depleting anti-CD4 monoclonal antibody (mAb) significantly inhibited allograft rejection. This study was undertaken to further examine the contribution of CD8 and CD4 T cells to the rejection of intestinal allografts. METHODS: Intestinal allografts from B6C3F1/J (C57BL/6 x C3H/HeJ) mice were transplanted into C57BL/6 recipients. Recipient groups included mice with an acquired deficiency in CD8 or CD4 T cells caused by treatment with depleting mAb or mice genetically deficient in CD8 or CD4 T cells as a result of disruption of the genes encoding major histocompatibility complex (MHC) class I, MHC class II, CD8, or CD4. In all cases, rejection was assessed histologically at predetermined time points. In some recipient groups, graft function was also assessed using a maltose absorption assay. RESULTS: Rejection, assessed between days 10 and 28 after transplantation, was significantly inhibited in mice deficient in CD8 or CD4 T cells after treatment with depleting mAb. In contrast, mice genetically deficient in either CD8 T cells (MHC class I or CD8 knockouts) or CD4 T cells (MHC class II or CD4 knockouts) rejected intestinal allografts promptly. Both histologic and functional evaluation of anti-CD8 mAb-treated mice on day 60 showed that the inhibition of rejection persisted even after the return of a substantial number of CD8 T cells. Although intestinal allografts from anti-CD8 mAb-treated mice displayed little to no evidence of rejection on day 60 after transplantation, these mice were able to reject both donor and third-party skin grafts. CONCLUSIONS: These results demonstrate that the inhibition of intestinal allograft rejection associated with mAb treatment is not attributable solely to depletion of CD8 or CD4 T cells. Furthermore, anti-CD8 mAb administration did not induce donor-specific tolerance or cause nonspecific immune suppression, as indicated by the skin-grafting experiments. Our findings suggest that at least some depleting mAbs mediate their protective effect on allograft rejection via an alternative mechanism such as the induction of a regulatory cell population(s).

Animals↗

PubMed2000

Interleukin-2 and interferon-gamma double knockout mice reject heterotopic cardiac allografts.

BACKGROUND: Several studies suggest that MHC-mismatched allografts reject with a Th1 or Th2 immune response, but these models all have low-level expression of the Th1 cytokines interleukin (IL)-2 and interferon-gamma (IFN-gamma). METHODS: We interbred mice with single targeted gene disruptions for IL-2 and IFN-gamma to establish IL-2 + IFN-gamma double knockout (DKO) mice. Heterotopic cardiac allografts from DBA/2j (H2d) donors were transplanted WT, IL-2 knockout (KO), IFN-gamma KO, and DKO recipients (C57BL/6x129; H2b). Cytokine transcripts from allografts and DKO splenocytes were analyzed by reverse transcription polymerase chain reaction. RESULTS: DKO mice had a cytokine profile and IgG1/ IgG2a isotype ratio characteristic of Th2 deviation. DKO recipients rejected heterotopic cardiac allografts faster than IL-2 KO mice, but significantly slower than WT and IFN-gamma KO mice (P<0.01). Analysis of the rejecting DKO recipients showed intragraft Th2 cytokine expression. CONCLUSION: The combined absence of IL-2 and IFN-gamma in the setting of Th2 deviation does not prevent allograft rejection.

Animals↗

PubMed2001

Amphetamine-induced locomotor activation in 5-HT(1B) knockout mice: effects of injection route on acute and sensitized responses.

Knockout mice lacking serotonin(1B) (5-hydroxytryptamine(1B); 5-HT(1B)) receptors (1BKO) exhibit increased sensitivity to the stimulant and reinforcing effects of indirect dopamine (DA) agonists and are more reactive to mild stressors such as handling and the injection procedures that commonly occur when using the intraperitoneal (i.p.) route of drug administration. Since the intravenous (i.v.) route of administration allows minimal handling and injection-induced stress, the present study was designed to evaluate the effect of the administration route on amphetamine-induced locomotor activation and behavioural sensitization in 1BKO mice. For this purpose, 1BKO and wild-type (WT) control mice were administered i.p. or i.v. amphetamine in a within-session design, which allows evaluation of a complete dose-response curve within a single session. The locomotor stimulant effects of i.p. (0.5-4.0 mg/kg) and i.v. (0.6-1.2 mg/kg) amphetamine were investigated both acutely and following repeated treatments (four treatments at 48 h intervals). The results showed that acute i.p. amphetamine injection induced a significant higher horizontal activity peak effect in 1BKO mice, while this difference was less profound after acute i.v. injection. However, repeated i.p. or i.v. administration of amphetamine induced significantly higher locomotion in 1BKO mice. We conclude that the stimulant effects of amphetamine can be influenced by the route of administration in a genotype-dependent manner, and that route of drug administration (and associated variables) should be considered an important factor in studies of psychostimulant action in knockout mice.

Amphetamine↗

PubMed1998

Endothelial-perivascular cell signaling in vascular development: lessons from knockout mice.

The importance of perivascular-endothelial cell interactions during blood vessel development is discussed in the light of recent findings in platelet-derived growth factor-B, platelet-derived growth factor receptor-beta, angiopoietin-1 and tie-2 knockout mice, which all show deficient development of perivascular cells. The initial formation of networks of endothelial tubes (vasculogenesis) does not seem to depend on the perivascular cells but subsequent vessel remodeling relies on mesenchymal-endothelial short-range signaling. Based on findings in platelet-derived growth factor and platelet-derived growth factor receptor knockout mice, a general model for the role of platelet-derived growth factors in smooth muscle development is proposed.

Angiopoietin-1↗

PubMed2006

Pressure overload causes cardiac hypertrophy in beta1-adrenergic and beta2-adrenergic receptor double knockout mice.

OBJECTIVE: Cardiac hypertrophy arises as an adaptive response to increased afterload. Studies in knockout mice have shown that catecholamines, but not alpha1-adrenergic receptors, are necessary for such an adaptation to occur. However, whether beta-adrenergic receptors are critical for the development of cardiac hypertrophy in response to pressure overload is not known at this time. METHODS AND RESULTS: Pressure overload was induced by transverse aortic banding in beta1-adrenergic and beta2-adrenergic receptor double knockout (DbetaKO) mice, in which the predominant cardiac beta-adrenergic receptor subtypes are lacking. Chronic pressure overload for 4 weeks induced cardiac hypertrophy in both DbetaKO and wild-type mice. There were no significant differences between banded mice in left ventricular weight to body weight ratio, in the left ventricular wall thickness, in the cardiomyocyte size or in the expression levels of the load-sensitive cardiac genes such as ANF and beta-MHC. Additionally, the left ventricular systolic pressure, an index of afterload, and cardiac contractility, evaluated as dp/dtmax, the maximal slope of systolic pressure increment, and Ees, end-systolic elastance, were increased at a similar level in both wild-type and DbetaKO banded mice, and were significantly greater than in sham controls. CONCLUSION: Despite chronic activation of the cardiac beta-adrenergic system being sufficient to induce a pathological hypertrophy, we show that beta1-adrenergic and beta2-adrenergic receptors are not an obligatory component of the signaling pathway that links the increased afterload to the development of cardiac hypertrophy.

Animals↗

PubMed2005

Sexual receptivity is reduced in the female mu-opioid receptor knockout mouse.

Activation of mu-opioid receptors is critical to steroid regulation of female sexual behavior, lordosis, in rodents. Estrogen treatment activates mu-opioid receptors in the medial preoptic area inhibiting lordosis, but ultimately appears important for progesterone facilitation of lordosis. We investigated the role of mu-opioid receptors in the expression of sexual receptivity in mice lacking mu-opioid receptors. Although estrogen and progesterone facilitated lordosis in mu-opioid receptor knockout mice, they exhibited deficits in lordosis quotient and score compared with wild-type females, indicating reduced sexual receptivity. In contrast, wild-type and mu-opioid receptor knockout female mice did not differ in either active or passive avoidance of the male. These data are most consistent with the hypothesis that mu-opioid receptor activation is necessary for estrogen and progesterone to maximally facilitate lordosis.

Animals↗

PubMed2006

Thalamic calcification in vitamin D receptor knockout mice.

Vitamin D is a steroid hormone with many important functions in the brain, mediated through the nuclear vitamin D receptor. Here, we report that aging nuclear vitamin D receptor knockout mice demonstrate a symmetric thalamic calcification with numerous Ca/P-containing laminated bodies. These results are consistent with clinical findings showing brain calcification in patients with vitamin D deficiency. Our results suggest that nuclear vitamin D receptor deficiency leads to brain mineralization in vitamin D receptor knockout mice, which may represent an experimental model of intracranial calcification.

Age Factors↗

PubMed2006

Abolition of sex-dependent effects of prenatal exposure to diethylstilbestrol on emotional behavior in estrogen receptor-alpha knockout mice.

To investigate the contribution of estrogen receptor-alpha in the effects of prenatal exposure to diethylstilbestrol on emotionality, estrogen receptor-alpha knockout heterozygous pregnant mice were orally given 0.1 microg/animal of diethylstilbestrol from gestational day 11 to 17. Emotional behavior of the offspring was assessed at 5 weeks in light-dark transition tests. Time spent in the light area was significantly decreased (i.e. decrease of emotionality) by diethylstilbestrol exposure in wild-type female mice, whereas in wild-type male mice this measurement tended to be increased (i.e. increase of emotionality) by diethylstilbestrol treatment. These sex-dependent effects of diethylstilbestrol were completely abolished in estrogen receptor-alpha knockout mice. These results suggest that the sex-dependent effects of diethylstilbestrol on emotionality are mainly produced by its action on estrogen receptor-alpha.

Animals↗

PubMed2002

Y4 receptor knockout rescues fertility in ob/ob mice.

Hypothalamic neuropeptide Y (NPY) has been implicated in the regulation of energy balance and reproduction, and chronically elevated NPY levels in the hypothalamus are associated with obesity and reduced reproductive function. However, it is not known which one of the five cloned Y receptors mediates these effects. Here we show that crossing the Y4 receptor knockout mouse (Y4(-/-)) onto the ob/ob background restores the reduced plasma testosterone levels of ob/ob mice as well as the reduced testis and seminal vesicle size and morphology to control values. Fertility in the sterile ob/ob mice was greatly improved by Y4 receptor deletion, with 100% of male and 50% of female Y4(-/-),ob/ob double knockout mice producing live offspring. Development of the mammary ducts and lobuloalveoli was significantly enhanced in pregnant Y4(-/-) and Y4(-/-),ob/ob females. Consistent with the improved fertility and enhanced mammary gland development, gonadotropin releasing hormone (GnRH) expression was significantly increased in Y4(-/-) and Y4(-/-),ob/ob animals. Y4(-/-) mice displayed lower body weight and reduced white adipose tissue mass accompanied by increased plasma levels of pancreatic polypeptide (PP). However, Y4 deficiency had no beneficial effects to reduce body weight or excessive adiposity of ob/ob mice. These data suggest that central Y4 receptor signaling specifically inhibits reproductive function under conditions of elevated central NPY-ergic tonus.

Adipose Tissue↗

PubMed1998

Piroxicam and acarbose as chemopreventive agents for spontaneous intestinal adenomas in APC gene 1309 knockout mice.

The use of nonsteroidal anti-inflammatory drugs has been suggested to have a chemopreventive effect against colon carcinoma, through the inhibition of cyclooxygenases 1 and 2, in patients with familial adenomatous polyposis and in animal models. Acarbose, an alpha-glycosidase inhibitor, may also be chemopreventive. In order to examine the effects of these drugs we employed APC gene knockout mice randomized into 3 groups, one for treatment with piroxicam (0.05% concentration in drinking water), one for acarbose (0.04% concentration in food) and another for the control. After 14 weeks of treatment, mice were killed for quantitation of gastric and intestinal adenomas. Tumor multiplicity in the whole gastrointestinal tract decreased from 33.89 +/- 13.07 tumors/mouse in the control group to 17.05 +/- 7 tumors/mouse in the piroxicam-treated group (P < 0.001). The decrease in the acarbose-treated group (29.68 +/- 12.86 tumors/mouse) was not significant (P < 0.05). The number of tumors > or = 3 mm in diameter was also quantified in all gastrointestinal segments. The number of such tumors in the piroxicam group was decreased to 0.56 +/- 1.2 tumors/mouse from the control value of 3.78 +/- 1.17 tumors/mouse (P < 0.001), while in the acarbose-treated group the number decreased to 2.36 +/- 1.7 tumors/mouse (P < 0.01). Thus, piroxicam decreases the size and number of gastrointestinal adenomas in APC 1309 knockout mice, while acarbose decreases only the size.

Acarbose↗