Biomedical subjects

Linda A Jelicks

Publications and source records attributed to Linda A Jelicks.

At least 19 recordsLinked to original sources

PubMed2006

Cell cycle regulatory proteins in the liver in murine Trypanosoma cruzi infection.

The liver is an important target of Trypanosoma cruzi infection. Infection of CD-1 mice with T. cruzi (Brazil strain) resulted in parasitism of the liver, primarily in sinusoidal and Kupffer cells. Immunoblot analysis revealed activation of extra cellular signal-regulated kinase (ERK) during the acute and subacute period of infection, but p38 mitogen activated kinase (MAPK) and JNK were not activated. The activity of important cell cycle regulatory genes was also examined in the liver following infection. There was increased expression of cyclin D1, cyclin E and cyclin A as well as proliferating cell nuclear antigen (PCNA) at 45, 60 and 215 days post infection. In addition, the levels of the cyclin-dependent kinase inhibitors p27(KIP1), p21(WAF1) and the tumor suppressor p53 were increased in the livers obtained from infected mice. Quantitative PCR revealed increased abundance of mRNA for cyclins A, D1 and E. Interestingly, cyclin A and E are ordinarily not found in the adult liver. Thus infection caused a reversion to a fetal/neonatal phenotype. These data provide a molecular basis for cell proliferation in the liver following T. cruzi infection.

Animals↗

PubMed2006

Role of transcription factor NFAT in glucose and insulin homeostasis.

Compromised immunoregulation contributes to obesity and complications in metabolic pathogenesis. Here, we demonstrate that the nuclear factor of activated T cell (NFAT) group of transcription factors contributes to glucose and insulin homeostasis. Expression of two members of the NFAT family (NFATc2 and NFATc4) is induced upon adipogenesis and in obese mice. Mice with the Nfatc2-/- Nfatc4-/- compound disruption exhibit defects in fat accumulation and are lean. Nfatc2-/- Nfatc4-/- mice are also protected from diet-induced obesity. Ablation of NFATc2 and NFATc4 increases insulin sensitivity, in part, by sustained activation of the insulin signaling pathway. Nfatc2-/- Nfatc4-/- mice also exhibit an altered adipokine profile, with reduced resistin and leptin levels. Mechanistically, NFAT is recruited to the transcription loci and regulates resistin gene expression upon insulin stimulation. Together, these results establish a role for NFAT in glucose/insulin homeostasis and expand the repertoire of NFAT function to metabolic pathogenesis and adipokine gene transcription.

AMP-Activated Protein Kinases↗

PubMed2006

Dyskinesis in Chagasic myocardium: centerline analysis of wall motion using cardiac-gated magnetic resonance images of mice.

We report on the use of centerline analysis of cardiac-gated magnetic resonance images to measure wall motion abnormalities in mice infected with Trypanosoma cruzi. To our knowledge, this is the first report of segmental wall motion abnormalities in an animal model of Chagas' disease. Chagas' disease patients with severe cardiac involvement exhibit mild hypokinesis in an extensive region of the left ventricle and dyskinesis in the apical region. We observed dyskinetic segments in a similar region of the hearts of infected wild-type mice. Dyskinesis was not observed in infected mice lacking macrophage inflammatory protein-1alpha, a chemokine that may play an important role in the cardiac remodeling that is normally observed in mouse models of Chagas' disease and in human patients. This study aimed to demonstrate the utility of cardiac-gated magnetic resonance imaging and centerline analysis as a straightforward method for monitoring regional left ventricular wall motion in transgenic and/or diseased mice.

Animals↗

PubMed2005

Risedronate in the treatment of Murine Chagas' disease.

Risedronate, a bisphosphonate, was used to treat CD-1 mice infected with the Brazil strain of Trypanosoma cruzi. When given by subcutaneous injection 3 times/week, there was a significant reduction in mortality, however, the myocardial pathology and right ventricular dilation was unchanged in these mice compared to control animals. In C57BL/6 mice infected with the Tulahuen strain, there was no change in mortality in response to risedronate treatment. These data suggest that this class of compounds has activity against T. cruzi in vivo and illustrate the utility of imaging and pathologic studies as adjuncts in the evaluation of therapeutic compounds as treatments for experimental Chagas' disease. In addition, it underscores the need to use different strains of T. cruzi.

Animals↗

PubMed2005

The adipocyte as an important target cell for Trypanosoma cruzi infection.

Adipose tissue plays an active role in normal metabolic homeostasis as well as in the development of human disease. Beyond its obvious role as a depot for triglycerides, adipose tissue controls energy expenditure through secretion of several factors. Little attention has been given to the role of adipocytes in the pathogenesis of Chagas disease and the associated metabolic alterations. Our previous studies have indicated that hyperglycemia significantly increases parasitemia and mortality in mice infected with Trypanosoma cruzi. We determined the consequences of adipocyte infection in vitro and in vivo. Cultured 3T3-L1 adipocytes can be infected with high efficiency. Electron micrographs of infected cells revealed a large number of intracellular parasites that cluster around lipid droplets. Furthermore, infected adipocytes exhibited changes in expression levels of a number of different adipocyte-specific or adipocyte-enriched proteins. The adipocyte is therefore an important target cell during acute Chagas disease. Infection of adipocytes by T. cruzi profoundly influences the pattern of adipokines. During chronic infection, adipocytes may represent an important long-term reservoir for parasites from which relapse of infection can occur. We have demonstrated that acute infection has a unique metabolic profile with a high degree of local inflammation in adipose tissue, hypoadiponectinemia, hypoglycemia, and hypoinsulinemia but with relatively normal glucose disposal during an oral glucose tolerance test.

3T3-L1 Cells↗

PubMed2005

Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment.

The interactions of transformed cells with the surrounding stromal cells are of importance for tumor progression and metastasis. The relevance of adipocyte-derived factors to breast cancer cell survival and growth is well established. However, it remains unknown which specific adipocyte-derived factors are most critical in this process. Collagen VI is abundantly expressed in adipocytes. Collagen(-/-) mice in the background of the mouse mammary tumor virus/polyoma virus middle T oncogene (MMTV-PyMT) mammary cancer model demonstrate dramatically reduced rates of early hyperplasia and primary tumor growth. Collagen VI promotes its growth-stimulatory and pro-survival effects in part by signaling through the NG2/chondroitin sulfate proteoglycan receptor expressed on the surface of malignant ductal epithelial cells to sequentially activate Akt and beta-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VIalpha3, a proteolytic product of the full-length molecule, are dramatically upregulated in murine and human breast cancer lesions. The same fragment exerts potent growth-stimulatory effects on MCF-7 cells in vitro. Therefore, adipocytes play a vital role in defining the ECM environment for normal and tumor-derived ductal epithelial cells and contribute significantly to tumor growth at early stages through secretion and processing of collagen VI.

Adipocytes↗

PubMed2005

Caveolin-3 knockout mice show increased adiposity and whole body insulin resistance, with ligand-induced insulin receptor instability in skeletal muscle.

Caveolin-3 (Cav-3) is expressed predominantly in skeletal muscle fibers, where it drives caveolae formation at the muscle cell's plasma membrane. In vitro studies have suggested that Cav-3 may play a positive role in insulin signaling and energy metabolism. We directly address the in vivo metabolic consequences of genetic ablation of Cav-3 in mice as it relates to insulin action, glucose metabolism, and lipid homeostasis. At age 2 mo, Cav-3 null mice are significantly larger than wild-type mice, and display significant postprandial hyperinsulinemia, whole body insulin resistance, and whole body glucose intolerance. Studies using hyperinsulinemic-euglycemic clamps revealed that Cav-3 null mice exhibited 20% and 40% decreases in insulin-stimulated whole body glucose uptake and whole body glycogen synthesis, respectively. Whole body insulin resistance was mostly attributed to 20% and 40% decreases in insulin-stimulated glucose uptake and glucose metabolic flux in the skeletal muscle of Cav-3 null mice. In addition, insulin-mediated suppression of hepatic glucose production was significantly reduced in Cav-3 null mice, indicating hepatic insulin resistance. Insulin-stimulated glucose uptake in white adipose tissue, which does not express Cav-3, was decreased by approximately 70% in Cav-3 null mice, suggestive of an insulin-resistant state for this tissue. During fasting, Cav-3 null mice possess normal insulin receptor protein levels in their skeletal muscle. However, after 15 min of acute insulin stimulation, Cav-3 null mice show dramatically reduced levels of the insulin receptor protein, compared with wild-type mice treated identically. These results suggest that Cav-3 normally functions to increase the stability of the insulin receptor at the plasma membrane, preventing its rapid degradation, i.e., by blocking or slowing ligand-induced receptor downregulation. Thus our results demonstrate the importance of Cav-3 in regulating whole body glucose homeostasis in vivo and its possible role in the development of insulin resistance. These findings may have clinical implications for the early diagnosis and treatment of caveolinopathies.

Adipose Tissue↗

PubMed2005

A biphasic response of hepatobiliary cholesterol metabolism to dietary fat at the onset of obesity in the mouse.

Human obesity is associated with abnormal hepatic cholesterol homeostasis and resistance to leptin action. Because leptin administration to rodents promotes the biliary elimination of plasma cholesterol, this study was designed to elucidate a pathophysiological role for leptin during the development of obesity. We fed mice diets containing high or low saturated fat contents. Before and after the onset of obesity, we measured downstream targets of leptin action and evaluated plasma, hepatic, and biliary cholesterol metabolism. Although not obese at 28 days, mice fed a high fat diet became hyperleptinemic. Sensitivity to leptin was evidenced by downregulation of both hepatic stearoyl CoA desaturase-1 and fatty acid synthase. Due principally to upregulation of adenosine triphosphate-binding cassette proteins A1 and G5, plasma high density lipoprotein (HDL) cholesterol concentrations increased, as did relative secretion rates of biliary cholesterol. A smaller, more hydrophilic bile salt pool decreased intestinal cholesterol absorption. In this setting, hepatic cholesterol synthesis was downregulated, indicative of increased uptake of plasma cholesterol. After 56 days of high fat feeding, obesity was associated with leptin resistance, as evidenced by marked hyperleptinemia without downregulation of stearoyl CoA desaturase-1 or fatty acid synthase and by upregulation of hepatic cholesterol and bile salt synthesis. Hypercholesterolemia was attributable to overproduction and decreased clearance of large HDL(1) particles. In conclusion, before the onset of obesity, preserved leptin sensitivity promotes biliary elimination of endogenous cholesterol in response to dietary fat. Leptin resistance due to obesity leads to a maladaptive response whereby newly synthesized cholesterol in the liver is eliminated via bile.

Animals↗

PubMed2005

MR imaging of caveolin gene-specific alterations in right ventricular wall thickness.

Caveolin-1 and caveolin-3 are expressed in the mammalian heart. Mice deficient in caveolin 1 or 3 exhibit cardiac abnormalities including left ventricular hypertrophy and reduced fractional shortening. Cardiac imaging technologies such as transthoracic echocardiography and cardiac-gated magnetic resonance imaging (MRI) are effective tools for the study of left ventricular morphology and function in mice; however, there has not been widespread use of these technologies in studies of right ventricular morphology. In particular, right ventricular wall thickness has been difficult to assess using cardiac imaging technologies. We report here the use of centerline analysis of cardiac-gated MR images to more accurately determine right ventricular wall thickness in the mouse heart. Right ventricular wall thickness was evaluated in Cav-1 null, Cav-3 null and Cav-1/3 null mice, as well as wild-type control mice. Using this technique, we find that caveolin null mice exhibit significant thickening of the right ventricular wall as compared with age-matched wild-type controls. Interestingly, right ventricular wall thickening is greatest in the Cav-1/3 null mice. Furthermore, significant right ventricular wall thickening is also seen in the Cav-1 null mice. Histological analyses revealed right ventricular hypertrophy consistent with the imaging results. These studies demonstrate the utility of MRI in determining right ventricular wall thickness and underscore the severity of the right ventricular hypertrophy in caveolin null mice.

Animals↗

PubMed2005

Trypanosoma cruzi infection induced changes in the innervation, structure and function of the murine bladder.

PURPOSE: The involvement of the lower urinary tract in chronic Chagas' disease has received little attention. Therefore, we investigated pathology and functional alterations in the bladder of Trypanosoma cruzi infected mice. MATERIALS AND METHODS: CD1 mice were infected with 5 x 10 T. cruzi trypomastigotes of the Brazil strain of T. cruzi. At day 100 after infection bladder structure and function were examined by pathological evaluation, magnetic resonance imaging and cystometric studies. RESULTS: The bladder in infected mice weighed more and were large, dilated, deformed, friable and thin walled compared with control mice. Magnetic resonance imaging confirmed these observations. Inflammation, fibrosis and ganglionitis was observed. Cystometric studies revealed that baseline, threshold and micturition pressures were increased in infected mice. Bladder overactivity and decreased bladder compliance were also noted in infected mice. There were no detectable differences in bladder capacity, micturition volume or residual volume between infected and uninfected mice. CONCLUSIONS: Bladder abnormalities may be a more common clinical sequelae of T. cruzi infection than previously appreciated.

Animals↗

PubMed2005

Role of endothelin 1 in the pathogenesis of chronic chagasic heart disease.

On the basis of previous observations, endothelin 1 (ET-1) has been suggested as contributing to the pathogenesis of Chagasic cardiomyopathy. Therefore, ET-1flox/flox;alpha-MHC-Cre(+) mice in which the ET-1 gene was deleted from cardiac myocytes and ET-1flox/flox;Tie 2 Cre(+) mice in which the ET-1 gene was deleted from endothelial cells were infected with Trypanosoma cruzi. Genetic controls for these cell-specific ET-1 knockout mice were used. Ninety percentage of all mice survived acute infection with the Brazil strain and were evaluated 130 days postinfection. Inflammation and fibrosis were observed in all infected mice; however, fibrosis was reduced in ET-1flox/flox;alpha-MHC-Cre(+) mice. Cardiac magnetic resonance imaging revealed that infection resulted in a significant increase in right ventricular internal diameter (RVID) in all mice except ET-1flox/flox;alpha-MHC-Cre(+) mice; i.e., RVID was not changed in infected ET-1flox/flox;alpha-MHC-Cre(+) mice. Echocardiography of the left ventricle demonstrated increased left ventricular end-diastolic diameter, reduced fractional shortening, and decreased relative wall thickness in infected mice. However, the magnitude of the changes was significantly less in ET-1flox/flox;alpha-MHC-Cre(+) mice compared to other groups. These data provide further evidence of a role for ET-1, particularly cardiac myocyte-derived ET-1, in the pathogenesis of chronic Chagasic cardiomyopathy.

Animals↗

PubMed2004

Effects of early and late verapamil administration on the development of cardiomyopathy in experimental chronic Trypanosoma cruzi (Brazil strain) infection.

Chagas' disease, caused by Trypanosoma cruzi, leads to acute myocarditis and chronic cardiomyopathy. Myocardial structure and function were evaluated in T. cruzi (Brazil strain)-infected CD1 mice by histopathology, cardiac gated magnetic resonance imaging (MRI) and transthoracic echocardiography. There was a significant reduction in inflammation and fibrosis in infected mice treated early in infection. In mice treated late in infection, echocardiography revealed a significant increase in the end diastolic diameter and a decrease in percent fractional shortening and relative wall thickness. MRI revealed an increase in the right ventricular internal dimension. These findings, consistent with a dilated cardiomyopathy, were ameliorated in the early but not in the late treatment group, demonstrating that late treatment with verapamil is ineffective in reversing the development of chagasic cardiomyopathy in chronically infected mice. Our data underscore the hypothesis that early events determine the progression to cardiomyopathy and that early treatment with verapamil can prevent such progression.

Animals↗

PubMed2003

Caveolin-1 null (-/-) mice show dramatic reductions in life span.

Caveolae are 50-100 nm flask-shaped invaginations of the plasma membrane found in most cell types. Caveolin-1 is the principal protein component of caveolae membranes in nonmuscle cells. The recent development of Cav-1-deficient mice has allowed investigators to study the in vivo functional role of caveolae in the context of a whole animal model, as these mice lack morphologically detectable caveolae membrane domains. Surprisingly, Cav-1 null mice are both viable and fertile. However, it remains unknown whether loss of caveolin-1 significantly affects the overall life span of these animals. To quantitatively determine whether loss of Cav-1 gene expression confers any survival disadvantages with increasing age, we generated a large cohort of mice (n = 180), consisting of Cav-1 wild-type (+/+) (n = 53), Cav-1 heterozygous (+/-) (n = 70), and Cav-1 knockout (-/-) (n = 57) animals, and monitored their long-term survival over a 2 year period. Here, we show that Cav-1 null (-/-) mice exhibit an approximately 50% reduction in life span, with major declines in viability occurring between 27 and 65 weeks of age. However, Cav-1 heterozygous (+/-) mice did not show any changes in long-term survival, indicating that loss of both Cav-1 alleles is required to mediate a reduction in life span. Mechanistically, these dramatic reductions in life span appear to be secondary to a combination of pulmonary fibrosis, pulmonary hypertension, and cardiac hypertrophy in Cav-1 null mice. Taken together, our results provide the first demonstration that loss of Cav-1 gene expression and caveolae organelles dramatically affects the long-term survival of an organism. In addition, aged Cav-1 null mice may provide a new animal model to study the pathogenesis and treatment of progressive hypertrophic cardiomyopathy and sudden cardiac death syndrome.

Aging↗

PubMed2003

A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity.

Adiponectin is a plasma protein expressed exclusively in adipose tissue. Adiponectin levels are linked to insulin sensitivity, but a direct effect of chronically elevated adiponectin on improved insulin sensitivity has not yet been demonstrated. We identified a dominant mutation in the collagenous domain of adiponectin that elevated circulating adiponectin values in mice by 3-fold. Adiponectinemia raised lipid clearance and lipoprotein lipase activity, and suppressed insulin-mediated endogenous glucose production. The induction of adiponectin during puberty and the sexual dimorphism in adult adiponectin values were preserved in these transgenic animals. As a result of elevated adiponectin, serum PRL values and brown adipose mass both increased. The effects on carbohydrate and lipid metabolism were associated with elevated phosphorylation of 5'-AMP-activated protein kinase in liver and elevated expression of peroxisomal proliferator-activated receptor gamma2, caveolin-1, and mitochondrial markers in white adipose tissue. These studies strongly suggest that increasing endogenous adiponectin levels has direct effects on insulin sensitivity and may induce similar physiological responses as prolonged treatment with peroxisomal proliferator-activated receptor gamma agonists.

3T3-L1 Cells↗

PubMed2003

Microarray analysis of changes in gene expression in a murine model of chronic chagasic cardiomyopathy.

Chagas' disease, caused by infection with Trypanosoma cruzi, is a major cause of cardiomyopathy in endemic regions. Infection leads to cardiac remodeling associated with congestive heart failure and dilated cardiomyopathy. In order to study the changes in the gene expression profile due to infection, C57BL/6 x 129sv male mice were infected with 1 x 10(3) trypomastigotes of the Brazil strain of T. cruzi. Histopathological examination of the myocardium revealed chronic inflammation, vasculitis and fibrosis 100 days post-infection. Cardiac magnetic resonance imaging revealed a significantly dilated heart compared with uninfected mice. The relative abundance or depletion of myocardial mRNAs was evaluated using high-density microarrays consisting of 27,400 mouse cDNAs, which were hybridized with fluorescent probes generated from mRNAs of T. cruzi infected and uninfected hearts. Differentially expressed genes were sorted according to their normalized expression patterns and functional groups including those involved in transcription, intracellular transport, structure/junction/adhesion or extracellular matrix, signaling, host defense, energetics, metabolism, cell shape and death. The regulated genes are interpreted in the pathogenesis of chagasic heart disease.

Animals↗

PubMed2003

Cardiovascular imaging in clinical and experimental acute infectious myocarditis.

Acute myocarditis can be caused by a variety of organisms. Congestive heart failure and death may occur as a consequence of these infections. In recent years cardiac imaging, by echocardiography and magnetic resonance and nuclear imaging has become a useful adjunct in the diagnosis and management of infectious myocarditis. Specific examples of their usefulness will be given in the discussions of chagasic myocarditis, bacterial myocarditis, acquired immunodeficiency syndrome and peripartum cardiomyopathy. Finally, we explore the exciting area of cardiac imaging of small animals, such as mice infected with Trypanosoma cruzi.

Acute Disease↗

PubMed2002

Caveolin-1 null mice develop cardiac hypertrophy with hyperactivation of p42/44 MAP kinase in cardiac fibroblasts.

Recently, development of a caveolin-1-deficient (Cav-1 null) mouse model has allowed the detailed analysis of caveolin-1's function in the context of a whole animal. Interestingly, we now report that the hearts of Cav-1 null mice are markedly abnormal, despite the fact that caveolin-1 is not expressed in cardiac myocytes. However, caveolin-1 is abundantly expressed in the nonmyocytic cells of the heart, i.e., cardiac fibroblasts and endothelia. Quantitative imaging studies of Cav-1 null hearts demonstrate a significantly enlarged right ventricular cavity and a thickened left ventricular wall with decreased systolic function. Histological analysis reveals myocyte hypertrophy with interstitial/perivascular fibrosis. Because caveolin-1 is thought to act as a negative regulator of the p42/44 MAP kinase cascade, we performed Western blot analysis with phospho-specific antibodies that only recognize activated ERK1/2. As predicted, the p42/44 MAP kinase cascade is hyperactivated in Cav-1 null heart tissue (i.e., interstitial fibrotic lesions) and isolated cardiac fibroblasts. In addition, endothelial and inducible nitric oxide synthase levels are dramatically upregulated. Thus loss of caveolin-1 expression drives p42/44 MAP kinase activation and cardiac hypertrophy.

Animals↗

PubMed2002

Caveolin-3 knock-out mice develop a progressive cardiomyopathy and show hyperactivation of the p42/44 MAPK cascade.

A growing body of evidence suggests that muscle cell caveolae may function as specialized membrane micro-domains in which the dystrophin-glycoprotein complex and cellular signaling molecules reside. Caveolin-3 (Cav-3) is the only caveolin family member expressed in striated muscle cell types (cardiac and skeletal). Interestingly, skeletal muscle fibers from Cav-3 (-/-) knock-out mice show a number of myopathic changes, consistent with a mild-to-moderate muscular dystrophy phenotype. However, it remains unknown whether a loss of Cav-3 affects the phenotypic behavior cardiac myocytes in vivo. Here, we present a detailed characterization of the hearts of Cav-3 knock-out mice. We show that these mice develop a progressive cardiomyopathic phenotype. At four months of age, Cav-3 knock-out hearts display significant hypertrophy, dilation, and reduced fractional shortening, as revealed by gated cardiac MRI and transthoracic echocardiography. Histological analysis reveals marked cardiac myocyte hypertrophy, with accompanying cellular infiltrates and progressive interstitial/peri-vascular fibrosis. Interestingly, loss of Cav-3 expression in the heart does not change the expression or the membrane association of the dystrophin-glycoprotein (DG) complex. However, a marker of the DG complex, alpha-sarcoglycan, was specifically excluded from lipid raft domains in the absence of Cav-3. Because activation of the Ras-p42/44 MAPK pathway in cardiac myocytes can drive cardiac hypertrophy, we next assessed the activation state of this pathway using a phospho-specific antibody probe. We show that p42/44 MAPK (ERK1/2) is hyperactivated in hearts derived from Cav-3 knock-out mice. These results are consistent with previous in vitro data demonstrating that caveolins may function as negative regulators of the p42/44 MAPK cascade. Taken together, our data argue that loss of Cav-3 expression is sufficient to induce a molecular program leading to cardiac myocyte hypertrophy and cardiomyopathy.

Animals↗