Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,693 records · Page 94Linked to original sources
PubMed2006

Functional integration of ecological networks through pathway proliferation.

Large-scale structural patterns commonly occur in network models of complex systems including a skewed node degree distribution and small-world topology. These patterns suggest common organizational constraints and similar functional consequences. Here, we investigate a structural pattern termed pathway proliferation. Previous research enumerating pathways that link species determined that as pathway length increases, the number of pathways tends to increase without bound. We hypothesize that this pathway proliferation influences the flow of energy, matter, and information in ecosystems. In this paper, we clarify the pathway proliferation concept, introduce a measure of the node-node proliferation rate, describe factors influencing the rate, and characterize it in 17 large empirical food-webs. During this investigation, we uncovered a modular organization within these systems. Over half of the food-webs were composed of one or more subgroups that were strongly connected internally, but weakly connected to the rest of the system. Further, these modules had distinct proliferation rates. We conclude that pathway proliferation in ecological networks reveals subgroups of species that will be functionally integrated through cyclic indirect effects.

Animals↗
PubMed2005

The MAP kinase pathway is upstream of the activation of GSK3beta that enables it to phosphorylate MAP1B and contributes to the stimulation of axon growth.

In pheochromocytoma 12 (PC12) cells and sympathetic neurons, nerve growth factor (NGF) engagement with the tropomyosin-related tyrosine kinase (TrkA) receptor activates the serine/threonine kinase glycogen synthase kinase 3beta (GSK3beta), enabling it to phosphorylate the microtubule-associated protein 1B (MAP1B). GSK3beta phosphorylation of MAP1B acts as a molecular switch to regulate microtubule dynamics in growing axons, and hence the rate of axon growth. An important question relates to the identification of the upstream pathway linking the activation of GSK3beta with TrkA engagement. TrkA can utilise a number of intracellular signalling pathways, including the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3 kinase (PI3K) pathway. We now show, using pharmacological inhibitor studies of PC12 cells and sympathetic neurons in culture and in vitro kinase and activation assays, that the MAPK pathway, and not the PI3K pathway, links NGF engagement with the TrkA receptor to GSK3beta activation in PC12 cells and sympathetic neurons. We also show that activated GSK3beta is a small fraction of the total GSK3beta present in developing brain and that it is not part of a multiprotein complex. Thus, NGF drives increased neurite growth rates partly by coupling the MAPK pathway to the activation of GSK3beta and thereby phosphorylation of MAP1B.

Animals↗
PubMed2005

Inhibition of the phosphatidylinositol 3'-kinase signaling pathway leads to decreased insulin-stimulated adiponectin secretion from 3T3-L1 adipocytes.

Adiponectin is a protein secreted by adipocytes, which modulates insulin resistance and is thought to confer protection from atherosclerosis. Decreased circulating adiponectin is seen in states of insulin resistance, yet the cause of this decrease remains unclear. We investigated the role of insulin in adiponectin secretion and the effect of selective insulin resistance on insulin-stimulated adiponectin secretion by 3T3-L1 adipocytes. Inhibition of the phosphatidylinositol 3'-kinase (PI3K) insulin-signaling pathway was induced with wortmannin (WT) or with a kinase-inactive Akt adenoviral construct (Akt-KD), and inhibition of the mitogen-activated protein kinase pathway was induced with PD98059 or with a dominant-negative ras adenoviral construct (DNras). The PI3K pathway was activated with a constitutively active Akt adenoviral construct (Akt-myr). Adiponectin was measured by Western blot, and adiponectin messenger RNA (mRNA) levels were determined by real-time reverse transcription-polymerase chain reaction. Insulin treatment increased adiponectin secretion and decreased intracellular adiponectin. Treatment with 100 nmol/L insulin for 24 hours resulted in a 78% increase in secreted adiponectin (P < .05). Insulin had no effect on adiponectin mRNA. WT or Akt-KD, but not PD98059 or DNras, inhibited insulin-stimulated adiponectin secretion (P < .05). Activation of the PI3K pathway resulted in increased insulin-independent adiponectin secretion. Inhibition of the PI3K- or mitogen-activated protein kinase-dependent pathway decreased adiponectin mRNA by 50% (P < .01). We demonstrate a decrease in insulin-stimulated adiponectin secretion with selective inhibition of the PI3K pathway. These results suggest a mechanism for the observed decreased adiponectin levels associated with insulin resistance, when defects in the PI3K-dependent insulin-signaling pathway lead to decreased adiponectin production, inadequate adiponectin secretion, and therefore low circulating adiponectin levels.

3T3-L1 Cells↗
PubMed2005

The concomitant expression and availability of conventional and alternative, cyanide-insensitive, respiratory pathways in Candida albicans.

The opportunistic oral pathogen Candida albicans expresses a cyanide-insensitive alternative oxidase (AOX) upon exposure to respiratory inhibitors that act downstream from coenzyme Q, and upon ageing of cells. To investigate whether the conventional pathway is retained when the alternative pathway is induced, cells were grown in the presence of sodium cyanide, a reversible inhibitor of cytochrome oxidase. AOX expression was monitored by Western blotting and the presence of cytochromes associated with complexes III and IV of the conventional pathway was monitored by recording spectra between 500 and 650 nm at 77K. The activities of complexes III and IV were determined in polarographic and enzyme-kinetic experiments using specific respiratory substrates and inhibitors. Results indicated that complexes III and IV are constitutively expressed and are functional in cells expressing AOX. Furthermore, the enzymatic activities of complexes III and IV were similar in mitochondrial preparations from cells grown with or without cyanide. We next investigated whether both pathways are simultaneously available for electron transfer from the Q pool to molecular oxygen. Respiration was virtually completely inhibited by the combination of cyanide and salicyl hydroxamic acid (SHAM) or antimycin A and SHAM, but only partly inhibited by either of these inhibitors alone. This indicates that electrons can in principle flow either through the conventional or the alternative respiratory pathway. The availability of two electron pathways in C. albicans and the potential use of either pathway endows this pleomorphic fungus with another level at which it can rapidly adjust to altered environmental conditions.

Antimycin A↗
PubMed2005

SAGE reveals expression of Wnt signalling pathway members during mouse prostate development.

To identify genes and pathways not previously implicated in the mesenchymal-epithelial (M/E) interactions that are critical for normal mouse prostate development, we constructed six serial analysis of gene expression (SAGE) libraries. Bioinformatic analyses revealed expression of various members of numerous signalling pathways and the differential expression of several members of the wingless-related MMTV integration site (Wnt) signalling pathway. This pathway has not been previously implicated in prostate development thus expression of selected Wnt pathway members in the developing prostate was confirmed by RT-qPCR. Of particular interest, an antagonist of the Wnt pathway, secreted frizzled related protein 2 (Sfrp2), was highly expressed in the early prostate libraries and down regulated at later developmental stages. The expression levels of four Wnt ligands reported to interact with Sfrp2 were, therefore, examined by RT-qPCR. We found that only Wnt4 transcripts were detectable in the developing prostate. Expression of Sfrp2 was validated using RT-qPCR and localization of Sfrp2 transcripts and protein was carried out using in situ hybridization and immunofluorescence, respectively. These studies provide the first evidence that Wnt pathway members are expressed in the developing prostate. Functional analyses are now required to establish the biological significance of this observation.

Animals↗
PubMed2004

The alternative pathway of complement in disease: opportunities for therapeutic targeting.

The alternative pathway of complement is receiving increasing attention as a therapeutic target because of recent findings in several animal models that support its essential role in tissue injury and disease pathogenesis. Although the contribution of alternative pathway activation to serum complement activation in vitro is relatively modest, its role in generating activated pro-inflammatory fragments at extra-vascular sites is substantial. Several potential mechanisms might underlie this exaggerated effect, including local synthesis of alternative pathway components, disease-induced alterations of regulatory proteins, and influx of inflammatory cells that contain alternative pathway components into sites of injury. This review examines several animal models in which the alternative pathway is centrally involved in disease pathogenesis and which suggest a potential role for alternative pathway inhibitors as therapies for human disease. It is also expected that several clinically relevant studies will be presented at the XXth International Complement Workshop that will identify additional areas of interest with regard to this pathway.

Animals↗
PubMed2006

The role of the phosphatidylinositide 3-kinase-protein kinase B pathway in schizophrenia.

Neuroanatomical studies of brains from schizophrenic patients report evidence for neuronal dystrophy, while in genetic studies in schizophrenia there is evidence for mutations in growth factors and the downstream enzymes phosphatidylinositide 3-kinase (PI3K) and protein kinase B (PKB). Since the PI3K-PKB pathway is involved in cellular growth and proliferation, reduced activity of this cascade in schizophrenia could at least partly explain the neuronal dystrophy. Risk factors for schizophrenia, such as corticosteroids and cannabis, suppress the activity of the PI3K-PKB pathway. Conversely, estrogen and vitamin D, 2 factors with a moderate protective activity in schizophrenia, electroconvulsive shock therapy, and chronic treatment with antipsychotic compounds stimulate the pathway. Reduced activity of the PI3K-PKB pathway makes the brain more susceptible to virus infections, anoxia, and obstetric complications (recognized risk factors for schizophrenia), whereas a diminution of growth factor levels towards the end of puberty could contribute to an increase in schizophrenia symptoms observed around that time. On the other hand, constitutive (over)activation of the PI3K-PKB pathway increases cancer risk. Consequently, the presumed hypoactivity of the PI3K-PKB cascade might provide a partial explanation for the remarkable epidemiological finding of a reduced cancer rate in schizophrenic patients. Recognition of the role of a dysfunctional PI3K-PKB pathway in schizophrenia might help in the discovery of hitherto undetected causative gene mutations and could also lead to novel therapeutic approaches. However, a major challenge that remains to be solved is how the PI3K-PKB pathway can be activated without increasing the risk of cancer.

Animals↗
PubMed2005

Measuring pathways to care in first-episode psychosis: a systematic review.

BACKGROUND: Adequately understanding and measuring pathways to care is a prerequisite for early detection and effective treatment of first-episode psychosis. METHOD: We conducted a systematic review of studies on pathways to care in first-episode psychosis to establish what measures currently exist to assess pathways in first-episode psychosis and to compare these measures. RESULTS: We identified 15 studies which had used six different measures of pathways to care. Differences in aims, methodology and lack of psychometric data did not allow a direct comparison of pathways measures but certain common themes emerged. DISCUSSION: Pathways to care in first-episode psychosis are diverse and varied. There is no measure with established psychometric properties that has been devised on a well-developed theoretical or conceptual framework and had its psychometric properties established. The conflict between exploring the patient's narrative and journey through the healthcare system and developing an empirical measure of pathways with optimal outcomes has hindered the development of such a measure.

Antipsychotic Agents↗
PubMed2004

Relevance of the palatal protein kinase A pathway to the pathogenesis of cleft palate by secalonic acid D in mice.

Secalonic acid-D (SAD) is a teratogenic mycotoxin inducing cleft palate (CP) in the offspring of the exposed mice by reducing palatal shelf size secondary to reduced proliferation of the palatal mesenchymal (PM) cells. Co-administration of dimethylsulfoxide (DMSO) reversed the CP-inducing effect of SAD. Although SAD has been shown to affect both protein kinases A (PKA) and C (PKC) pathways, the relevance of each of these pathways to its CP induction is unknown. The present studies were designed to test the hypothesis that the protective effect of DMSO is mediated by its specific reversal of the effect(s) of SAD on one of these two pathways using ELISA-based activity assays, Western blot analysis, electrophoretic mobility shift assays (EMSA), and murine embryonic PM (MEPM) cell growth in culture. Within the PKA pathway, SAD inhibited the activity of the catalytic subunit of PKA and its migration into the nucleus, elevated phosphorylated cyclic AMP (cAMP) response element (CRE)-binding protein (pCREB) level, and reduced the binding of CREB to CRE. In the PKC pathway, SAD reduced the activity of PKC and the binding of transcription factors (TF) to 12-O-tetradecanoate-13 phorbol acetate-response element (TRE). SAD also inhibited MEPM cell growth and the expression of the CRE- and TRE-containing gene, proliferating cell nuclear antigen (PCNA). Reversal, by DMSO, of the effects of SAD on MEPM cell growth, on PCNA expression and on all components of the PKA, but not of PKC, pathway suggests that the perturbation of the PKA pathway by SAD is relevant to its induction of CP in mice.

Animals↗
PubMed2004

Multi-pathway control of the proliferation versus meiotic development decision in the Caenorhabditis elegans germline.

An important event in the development of the germline is the initiation of meiotic development. In Caenorhabditis elegans, the conserved GLP-1/Notch signaling pathway regulates the proliferative versus meiotic entry decision, at least in part, by spatially inhibiting genes in the gld-1 and gld-2 parallel pathways, which are proposed to either inhibit proliferation and/or promote meiotic development. Mutations that cause constitutive activation of the GLP-1 pathway, or inactivation of both the gld-1 and gld-2 parallel pathways, result in a tumorous germline in which all cells are thought to be proliferative. Here, to analyze proliferation and meiotic entry in wild-type and mutant tumorous germlines, we use anti-REC-8 and anti-HIM-3 specific antibodies as markers, which under our fixation conditions, stain proliferative and meiotic cells, respectively. Using these makers in wild-type animals, we find that the border of the switch from proliferation to meiotic entry is staggered in late-larval and adult germlines. In wild-type adults, the switch occurs between 19 and 26 cell diameters from the distal end, on average. Our analysis of mutants reveals that tumorous germlines that form when GLP-1 is constitutively active are completely proliferative, while tumors due to inactivation of the gld-1 and gld-2 pathways show evidence of meiotic entry. Genetic and time course studies suggest that a third pathway may exist, parallel to the GLD-1 and GLD-2 pathways, that promotes meiotic development.

Animals↗
PubMed2006

Interferon-gamma-induced dephosphorylation of STAT3 and apoptosis are dependent on the mTOR pathway.

Interferon-gamma (IFN-gamma) exhibits diverse biological activities, including control of cell growth and tumor suppression. Here, we report that the treatment of M12 cells, a human metastatic prostate cancer cell line, with IFN-gamma, resulted in marked inhibition of cell proliferation and induced apoptosis. These effects were not seen with either IFN-alpha or IFN-beta. M12 cells, like many other human cancer cells, contain constitutively activated signal transducer and activator of transcription 3 (STAT3). The basal levels of both Akt and ERK1/2 phosphorylation are also markedly elevated in M12 cells. Strikingly, IFN-gamma-induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine-phosphorylated STAT3 (pY-STAT3). The IFN-gamma-induced dephosphorylation of pY-STAT3, however, was inhibited when the mTOR pathway was specifically blocked by rapamycin. Inhibition of PI-3K with low-dose LY294002, or MAPK with PD98059 also suppressed the mTOR/p70 S6k pathway, and correlated with the blockage of IFN-gamma-induced dephosphorylation of pY-STAT3. Simultaneously, treatment with LY294002, PD98059, or rapamycin abolished IFN-gamma-induced apoptosis in M12 cells. The inhibition of the mTOR pathway, however, did not affect IFN-gamma-induced activation of STAT1 pathway, and suppression of STAT1 expression by siRNA had no effect on IFN-gamma-induced dephosphorylation of pY-STAT3. Taken together, these results demonstrate that an intact mTOR pathway is critical for IFN-gamma-induced suppression of pY-STAT3 and apoptosis. Our study thus provides novel insights into the contributions of signaling pathways other than the classical JAK/STAT1 pathway in the anti-proliferative, proapoptotic actions of IFN-gamma.

Apoptosis↗
PubMed2004

Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes.

gp130-dependent signaling is known to play a critical role in the onset of heart failure. In that regard, cardiotrophin-1 (CT-1) activates several signaling pathways via gp130, and induces hypertrophy in neonatal rat cardiomyocytes. Among the mediators activated by CT-1, STAT3 is thought to be important for induction of cell hypertrophy, though its precise function in the CT-1 signaling pathway is not fully understood. In the present study, therefore, to better understand the significance of STAT3 activity in CT-1 signaling, we infected cultured cardiomyocytes with adenoviral vectors harboring a dominant-negative STAT3 mutant or one of two endogenous negative regulators of cytokine signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways [suppressor of cytokine signaling (SOCS) 1 and 3] and then examined their effects on three indexes of CT-1-induced cell hypertrophy: protein synthesis, secretion of brain natriuretic peptide and changes in cell surface area. In control cells, CT-1-induced both STAT3 phosphorylation and cell hypertrophy. Overexpression of dominant-negative STAT3 mutant suppressed CT-1-induced STAT3 phosphorylation, but did not affect cell hypertrophy. On the other hand overexpression of SOCS1 or SOCS3 inhibited both CT-1-induced STAT3 phosphorylation and cell hypertrophy. CT-1 also induced phosphorylations of ERK1/2 and ERK5 in cardiomyocytes, and those, too, were suppressed by overexpression of SOCSs. CT-1-induced cell hypertrophy was suppressed by overexpression of a dominant-negative MEK5 mutant, and not by overexpression of a dominant-negative MEK1 mutant. These findings indicate that the major pathway responsible for the hypertrophic responses to CT-1 is not JAK-STAT3 pathway nor MEK1-ERK1/2 pathway, but MEK5-ERK5 pathway.

Animals↗
PubMed2004

Alternative pathways of galactose assimilation: could inverse metabolic engineering provide an alternative to galactosemic patients?

The galactose assimilation pathway has been extensively studied as an example of a genetic regulatory switch. Besides the importance of this pathway as a tool in basic biological research, unraveling its structure and regulation is also of major medical importance. Impairment of galactose assimilation is the cause of the genetic metabolic disease known as "galactosemia", while the in vivo activity of the pathway affects the production of glycans. The latter have been connected to tumor metastasis, anti-cancer drug resistance and various cardiovascular diseases. Despite the vast amount of studies, however, galactose assimilation and its interaction with other parts of the metabolic network have not been fully elucidated yet. In yeast and higher eukaryotes, it is still being studied as comprising only the linear Leloir pathway. Recent observations, however, indicate that alternative pathways of galactose assimilation identified in prokaryotes and fungi might also be present in yeast. Such a result is valuable per se, because it could lead to the discovery of these pathways in humans. Even more importantly, these pathways provide alternative phenotypes with known genetic fingerprints that can be used in the context of classical and inverse metabolic engineering to examine and treat the mechanisms of defects of galactose assimilation.

Animals↗
PubMed1996

Radiofrequency ablation therapy of the posteroseptal accessory pathway.

Among 652 patients with Wolff-Parkinson-White syndrome who underwent radiofrequency ablation in this laboratory, 139 (21%) were found to have a total of 146 posteroseptal accessory pathways. Ablation was conducted by the regular transvenous or transaortic approach; ablation from cardiac venous structures was used only if regular approaches were unsuccessful. Of the 146 posteroseptal accessory pathways, 94 were successfully ablated from the left posteroseptal region and 45 from the right posteroseptal region. In 3, successful ablation of the accessory pathway required delivery of the current to the proximal coronary sinus, and in 1 it required delivery of the current to both the atrial and ventricular aspects of the tricuspid valve at the right posteroseptum. Thus, the accessory pathway was successfully ablated in 143 (98%) of 146 instances or in 136 (98%) patients. In 3 patients, ablation was unsuccessful despite delivery of current to the left posteroseptum, the right posteroseptum, the proximal coronary sinus, and the middle cardiac vein. Seventy-seven (57%) patients with an initial success, including 9 patients with resumed preexcitation or recurrence of paipitations, underwent a follow-up electro-physiologic study 90 +/- 72 days after ablation. Of these 9 patients, the initial successful ablation site was the right posteroseptum in 7 and the left posteroseptum in 2. The accessory pathways were ablated successfully by subsequent trials in 8 patients, whereas in 1 the accessory pathway was severely damaged. Thus radiofrequency ablation of posteroseptal accessory pathways can be achieved by the regular transvenous or transaortic approach; delivery of current to the coronary sinus or middle cardiac vein is unnecessary in most patients.

Adult↗
PubMed1996

Atrioventricular node properties in patients with accessory pathways.

A study during the era of surgical ablation suggested that atrioventricular (AV) nodal conduction is faster in patients with accessory pathways than in controls. In the present study, AV nodal characteristics were studied in 30 patients who underwent radiofrequency ablation of an accessory pathway and compared to 23 control patients. Sinus cycle length, AH and HV intervals, AV block cycle length, ventriculoatrial (VA) block cycle length, AV nodal effective refractory period, and VA effective refractory periods were measured in control and postablation accessory pathway patients before and after autonomic blockade with 0.04 mg/kg of atropine and 0.2 mg/kg of propranolol. The mean sinus cycle length in the control and accessory pathway groups did not differ significantly at baseline (798 +/- 211 and 766 +/- 156 msec, respectively) or after autonomic blockade (654 +/- 98 and 649 +/- 108 msec, respectively). The mean AH interval in the accessory pathway group (77 +/- 15 msec) was significantly shorter than in the control group (91 +/- 22 msec; p < 0.05) at baseline; however, there was no difference after autonomic blockade. No other significant differences were observed between the accessory pathway and control groups. These results demonstrate that AV nodal properties of patients with accessory pathways are not significantly different from controls and suggest that previously reported differences may have been due to selection bias.

Adult↗
PubMed1980

Interruption of multiple accessory conduction pathways in the Wolff-Parkinson-White syndrome.

Of 35 patients with Wolff-Parkinson-White syndrome operated on, 5 were seen with two accesory conduction pathways each; all of these were successfully interrupted. In one patient, one accessory conduction pathway each was located in the right and left side of the heart; in the other 4, both pathways were confined to the right side. In 2 patients with unilateral (right side) multiple accessory conduction pathways, Ebstein's anomaly was also present. In 1 patient with Ebstein's anomaly, the second unilateral accessory conduction pathway was discovered intraoperatively and was successfully interrupted. The remaining 4 patients required a second operation to interrupt the other pathway. A delta wave completely different from the preoperative one appeared 4 to 10 days after interruption of the first major pathway, and the second operation was performed 14 days, 42 days, four months, or five years after the first operation. All 5 patients survived, and long-term follow-up revealed no signs of morbidity.

Adolescent↗
PubMed2002

Characterization of the mitochondrial respiratory pathways in Candida albicans.

Candida albicans is an opportunistic oral pathogen. The flexibility of this microorganism in response to environmental changes includes the expression of a cyanide-resistant alternative respiratory pathway. In the present study, we characterized both conventional and alternative respiratory pathways and determined their ADP/O ratios, inhibitor sensitivity profiles and the impact of the utilization of either pathway on susceptibility to commonly used antimycotics. Oxygen consumption by isolated mitochondria using NADH or malate/pyruvate as respiratory substrates indicated that C. albicans cells express both cytoplasmic and matrix NADH-ubiquinone oxidoreductase activities. The ADP/O ratio was higher for malate/pyruvate (2.2+/-0.1), which generate NADH in the matrix, than for externally added NADH (1.4+/-0.2). In addition, malate/pyruvate respiration was rotenone-sensitive, and an enzyme activity assay further confirmed that C. albicans cells express Complex I activity. Cells grown in the presence of antimycin A expressed the cyanide-insensitive respiratory pathway. Determination of the respiratory control ratio (RCR) and ADP/O ratios of mitochondria from these cells indicated that electron transport from ubiquinone to oxygen via the alternative respiratory pathway was not coupled to ATP production; however, an ADP/O ratio of 0.8 was found for substrates that donate electrons at Complex I. Comparison of antifungal susceptibility of C. albicans cells respiring via the conventional or alternative respiratory pathways showed that respiration via the alternative pathway does not reduce the susceptibility of cells to a series of clinically employed antimycotics (using Fungitest), or to the naturally occurring human salivary antifungal peptide, histatin 5.

Antifungal Agents↗
PubMed2003

Calcineurin-mediated pathway involved in the differentiated phenotype of smooth muscle cells.

The calcineurin-mediated pathway is involved in skeletal and cardiac hypertrophy and vascular development in vivo, but the relationship between this pathway and the phenotype of smooth muscle cells (SMCs) remains unknown. Using visceral SMCs in culture as a model system of differentiated SMCs, we investigated the role of the calcineurin-mediated pathway in maintaining the differentiated phenotype of SMCs, which depends on the insulin-like growth factor (IGF-I)-triggered activation of the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB(Akt)) pathway. Treatment with calcineurin inhibitors, cyclosporin A or FK506, or the forced expression of the natural calcineurin inhibitor, CAIN, induced SMC dedifferentiation. Notably, suppression of the promoter activities of the SMC molecular markers caldesmon and alpha1 integrin by blocking the PI3-K/PKB(Akt) pathway was rescued by the forced expression of constitutively active calcineurin Aalpha, suggesting that the calcineurin-mediated pathway is critical for maintaining the differentiated phenotype of SMCs and works downstream of the PI3-K/PKB(Akt) pathway.

Animals↗