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Biomedical subjects

Y Liu

Publications and source records attributed to Y Liu.

At least 559 records · Page 31Linked to original sources
PubMed2001

Selected contribution: Gender differences in the endothelin-B receptor contribution to basal cutaneous vascular tone in humans.

To test whether the contribution of endothelin-B (ET-B) receptors to resting vascular tone differs between genders, we administered the ET-B receptor antagonist BQ-788 into the forearm skin of 11 male and 11 female subjects by intradermal microdialysis. Skin blood flow was measured using laser-Doppler flowmetry at the microdialysis site. The probe was perfused with Ringer solution alone, followed by BQ-788 (150 nM) and finally sodium nitroprusside (28 mM) to effect maximal cutaneous vasodilation. Cutaneous vascular conductance (CVC) was calculated (laser-Doppler flowmetry/mean arterial pressure) and normalized to maximal levels (%max). In male subjects, baseline CVC was (mean +/- SE) 19 +/- 3%max and increased to 26 +/- 5%max with BQ-788 (P < 0.05 vs. baseline). In female subjects, baseline CVC was 13 +/- 1%max and decreased to 10 +/- 1%max in response to BQ-788. CVC responses to BQ-788 differed with gender (P < 0.05); thus the contribution of ET-B receptors to resting cutaneous vascular tone differs between men and women. In men, ET-B receptors mediate tonic vasoconstriction, whereas, in women, ET-B receptors mediate tonic vasodilation.

Adult↗
PubMed2001

Effects of alcohol on blood pressure and production of vascular aldosterone and corticosterone.

AIMS: The aims of this study were to search for the role of alcohol in blood pressure regulation in rats and to investigate the effects of alcohol on the production of vascular aldosterone and corticosterone. METHODS: Male Wistar rats received alcohol 0.7 g x kg(-1) x day(-1) (alcohol-treated group 1) or 1.4 g x kg(-1) x day(-1) (alcohol-treated group 2) or 2.1 g x kg(-1) x day(-1) (alcohol-treated group 3), orally, for 3 months, and blood pressure was monitored by a pressure transducer. Systolic blood pressure increased in Wistar rats treated with alcohol compared to control rats. Mesenteric artery perfusion ex vivo was performed and pressor responses to norepinephrine were determined. The pressor responses to norepinephrine in mesenteric arteries treated with alcohol were significantly increased. The perfusate from the mesenteric arteries was collected and applied to a Sep-Pak C 18 cartridge column for reverse-phase high-performance liquid chromatography and aldosterone and corticosterone levels were determined by radioimmunoassay, aldosterone was decreased but corticosterone was increased in the perfusate from arteries treated with alcohol. RESULTS: Reverse transcriptase polymerase chain reaction showed that alcohol inhibited the expression of 11beta-HSD2 and CYP11B2 mRNA in mesenteric arteries. CONCLUSIONS: These results reveal that alcohol is able to induce hypertension and provide evidence that alcohol inhibits the transcriptions of both 11beta-HSD2 and CYP11B2 in the vasculature, leading to lower aldosterone and higher corticosterone production in vessels, and increased vasoconstrictor responses to norepinephrine.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2001

Effects of long-term enalapril and losartan therapy of hypertension on cardiovascular aldosterone.

BACKGROUND: Plasma aldosterone escape is found during long-term angiotensin-converting enzyme inhibitor therapy. Evidence for aldosterone production in cardiovascular tissues raised the question of whether or not aldosterone escape occurs in these tissues. METHOD: Spontaneously hypertensive rats were treated with enalapril (20 mg/kg/day) and losartan (50 mg/kg/day) for 20 weeks; untreated spontaneously hypertensive and Wistar rats were used as positive and normal controls, respectively. Ex vivo mesenteric artery and heart perfusion, high-performance liquid chromatography, and radioimmunoassay for aldosterone were performed. RESULTS: The results showed that enalapril failed to significantly inhibit aldosterone production in mesenteric artery, myocardium and plasma. Losartan significantly inhibited aldosterone production to that of Wistar rats in the mesenteric artery, myocardium and plasma. CONCLUSION: This study provides the first evidence that long-term angiotensin-converting enzyme inhibition therapy induces aldosterone escape in hypertensive cardiovascular tissues, and angiotensin II subtype 1 receptor antagonist does not induce aldosterone escape in mesenteric artery, myocardium and plasma of spontaneously hypertensive rats.

Aldosterone↗
PubMed2001

Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window.

BACKGROUND AND PURPOSE: We examined the neuroprotective efficacy of moderate-dose human albumin therapy in acute focal ischemic stroke and defined the therapeutic window after stroke onset, within which this therapy would confer neurobehavioral and histopathological neuroprotection. METHODS: Sprague-Dawley rats were anesthetized with halothane/nitrous oxide and received 2-hour middle cerebral artery occlusion (MCAo) by a poly-L-lysine-coated intraluminal suture. Neurological status was evaluated during occlusion (60 minutes) and daily for 3 days after MCAo. In the dose-response study, human albumin doses of either of 0.63 or 1.25 g/kg or saline vehicle (5 mL/kg) were given intravenously immediately after suture removal. In the therapeutic window study, a human albumin dose of 1.25 g/kg was administered intravenously at 2 hours, 3 hours, 4 hours, or 5 hours after onset of MCAo. Three days after MCAo, brains were perfusion-fixed, and infarct volumes and brain swelling were determined. RESULTS: Moderate-dose albumin therapy significantly improved the neurological score at 24 hours, 48 hours, and 72 hours and significantly reduced total infarct volume (by 67% and 58%, respectively, at the 1.25- and 0.63-g/kg doses). Cortical and striatal infarct volumes were also significantly reduced by both doses. Brain swelling was virtually eliminated by albumin treatment. Even when albumin therapy (1.25 g/kg) was initiated as late as 4 hours after onset of MCAo, it improved the neurological score and markedly reduced infarct volumes in cortex (by 68%), subcortical regions (by 52%), and total infarct (by 61%). CONCLUSIONS: Moderate-dose albumin therapy markedly improves neurological function and reduces infarction volume and brain swelling, even when treatment is delayed up to 4 hours after onset of ischemia.

Acute Disease↗
PubMed2001

Magnetic and structural properties of electrochemically self-assembled Fe1-xCox nanowires.

Fe1-xCox (0 < or = x < or = 1) nanowires have been self-assembled by electrodeposition in porous alumina films. The crystal structure is bee at the Fe end. With increased addition of Co, the crystal structure remains bcc until about 67% addition of Co. At the Co end, the structure is a mixture of hcp and fcc. Magnetic studies show very high coercivities for the Fe-Co alloys in the bcc phase. For Fe0.67Co0.33 nanowires of diameter 9 nm, the coercivity is about 2900 Oe, whereas for Fe0.33Co0.67 nanowires, it is about 2850 Oe. Temperature and size dependence of magnetic properties show no indication of superparamagnetic effects down to wire diameters of 9 nm.

Aluminum Oxide↗
PubMed2001

Laminar flow inhibits TNF-induced ASK1 activation by preventing dissociation of ASK1 from its inhibitor 14-3-3.

The inflammatory cytokine TNF-alpha stimulates several presumed pro-atherogenic signaling events in endothelial cells (ECs), including activation of c-Jun NH(2)-terminal kinase (JNK) and induction of E-selectin. Here, we show that apoptosis signal-regulating kinase 1 (ASK1), a MAP kinase kinase kinase, is required for TNF-mediated JNK activation. TNF activates ASK1 in part by dissociating ASK1 from its inhibitor 14-3-3. Because the risk of atherosclerosis is decreased in regions of steady laminar flow, we hypothesized that laminar flow inhibits proinflammatory cytokine-mediated activation of JNK. Steady laminar flow inhibited both TNF activation of ASK1 and JNK. Inhibition of ASK1 by flow correlated with increased association of ASK1 with 14-3-3. A constitutively active form of ASK1 lacking the 14-3-3-binding site (ASK1-Delta NS967A) was not inhibited by flow. These data establish ASK1 as a target for flow-mediated inhibition of cytokine signaling and indicate a novel role for 14-3-3 as an anti-inflammatory mediator in ECs.

14-3-3 Proteins↗
PubMed2001

Transplantation of genetically modified fibroblasts expressing BDNF in adult rats with a subtotal hemisection improves specific motor and sensory functions.

OBJECTIVE: We have previously reported that grafting fibroblasts genetically modified to express brain-derived neurotrophic factor (BDNF) into a subtotal cervical hemisection site that destroys the entire lateral funiculus will promote regeneration of rubrospinal axons and growth of other axons, prevent atrophy and death of axotomized red nucleus neurons, and improve forelimb use during spontaneous vertical exploration. We have now extended these studies by using additional sensorimotor tests to examine recovery. METHODS: The range of tests used included those in which the intervention did not improve recovery, those in which the intervention was associated with recovery, and those that showed little deficit. The selected tasks tested both sensory and motor functions and both forelimb and forelimb function. We used the open-field locomotor rating scale (BBB), locomotion on a narrow beam, forelimb use during swimming, horizontal rope walking, and a somatosensory asymmetry (patch-removal) test. After testing during an 8-week recovery period, a second lesion was made just rostral to the initial lesion/transplant site to test the role of the transplant in recovery. The rats were then retested for a further 5 weeks after the repeated lesion. RESULTS: The horizontal rope, swim, and patch-removal tests were reliably sensitive to the subtotal hemisection injury. Fb/BDNF-transplanted animals recovered motor functions on the horizontal rope-crossing test, and this recovery was abolished by a second lesion just rostral to the first lesion/transplant. In the patch-removal test, the latency to contact the affected limb was shorter in Fb/BDNF-treated rats than in the control group, and this effect was completely abolished by a second lesion. CONCLUSIONS: The rope-crossing and patch-removal tests are particularly useful tasks for assessing the beneficial effects of BDNF-expressing grafts in this injury model.

Animals↗
PubMed2001

Modified immunoregulation associated with interferon-gamma treatment of rat glioma.

Little is known about modulation by cytokines of major histocompatibility complex (MHC) antigen expression on intracranial tumors in vivo. The ability of cytokines to up-regulate MHC class-1 (MHC-1) antigen expression was investigated first in vitro using three rat glioma cell lines. Immunohistochemistry showed that incubation with recombinant rat interferon-gamma (rrIFN-gamma) increased MHC-1 antigen expression in RG2, C6, and 9L cell lines. Flow cytometric analysis revealed different baseline levels of MHC-1 antigen expression in each line (RG2 lowest, C6 highest), and that these levels increased in all lines after stimulation with 100 U ml(-1) or more of rrIFN-gamma. The antitumor effect of rrIFN-gamma in vivo was evaluated by assessing survival of rats with implanted intracerebral RG2 gliomas after intracarotid infusion of rrIFN-gamma. A high dose of rrIFN-gamma (2.4 x 10(5) U kg(-1)) significantly increased the survival, compared to control (p < 0.02). Intracarotid pre-treatment with the bradykinin analogue RMP-7 did not further increase survival. Immunohistochemical staining of tumor sections after in vivo rrIFN-gamma, infusion showed no clear increase in MHC-1 antigen expression on tumor cells but increased staining for ED2 antigen within tumor tissue, presumably from perivascular cells with MHC class-2 antigen.

Animals↗
PubMed2001

Correlation between bradykinin-induced blood-tumor barrier permeability and B2 receptor expression in experimental brain tumors.

Localization of B2 receptors in brain tumor cells and microvessel endothelial cells of the brain tumors was investigated to study the differential sensitivity of brain tumors to bradykinin. The present study shows that B2 receptor expression levels vary in cultured RG2, C6 and 9L glioma cells as well as in the intracerebral tumors established with these cell lines in rats. The double immunohistochemical data indicate that B2 receptors are localized to tumor cells and not to the tumor capillaries. Immunostaining and Western blot analysis for B2 receptor showed that the B2 receptor expression was in the order C6 > RG2 > 9L. The permeability studies on RG2, C6 and 9L tumors in rats showed that C6 tumor had the highest increase (178%) in Ki (unidirectional transport across blood-brain barrier (BBB)/blood-tumor barrier (BTB)), while 9L tumor had the least increase of Ki (35%) over the control group, following intracarotid infusion of bradykinin. We found a positive correlation (r = 0.965, p < 0.001) between B2 receptor levels and bradykinin-induced increase in BTB permeability. We conclude that B2 receptors are localized to tumor cells and not to normal or tumor capillary endothelial cells. C6 tumor with highest B2 receptor expression was most responsive to bradykinin, while RG2 and 9L tumors with lower B2 receptor expression level were less sensitive to bradykinin with regard to BTB permeability.

Animals↗
PubMed2001

Repeated, short-term ischemia augments bradykinin-mediated opening of the blood-tumor barrier in rats with RG2 glioma.

The objective of this study was to investigate the effects of repeated, short-term ischemia on bradykinin-mediated permeability of the blood-brain barrier (BBB) and the blood-tumor barrier (BTB). The mechanism by which bradykinin transiently opens the BTB, involves B2 receptors, Ca2+ flux, nitric oxide (NO) and cyclic GMP (cGMP). Since global and focal cerebral ischemia are known to increase levels of brain nitric oxide synthase (bNOS) and endothelial nitric oxide synthase (eNOS) we tested the hypothesis that bradykinin may increase the BTB permeability to a greater extent under ischemic rather than nonischemic conditions. The vertebral arteries in female Wistar rats were coagulated immediately after intracerebral implantation of RG2 glioma. Short-term ischemia was produced in some rats by a modification of the four-vessel occlusion procedure for incomplete forebrain ischemia, in which the common carotid arteries were clamped daily for 15 min on days 7, 8 and 9 after tumor implantation, after which reperfusion was allowed. On day 10 after tumor implantation, bradykinin (10 microg kg(-1) min(-1)) or phosphate-buffered saline (PBS) was infused for 15 min into the right carotid artery of anesthetized, sham-operated (nonischemic controls) and ischemic rats, followed by an intravenous bolus (100 microCi kg(-1)) each of [14C]-iodo-antipyrine (IAP), [14C]-dextran or [14C]-aminoisobutyric acid (AIB) to measure regional cerebral blood flow (rCBF), blood volume, or unidirectional transfer constant Ki, respectively, by quantitative autoradiography. A single 15-min ischemic episode significantly decreased rCBF in the tumor center (158.9 +/- 17.33 in control vs. 58.78 +/- 24.45 ml 100 g(-1) min(-1) in ischemic group; p < 0.01) and in the tumor periphery (106.82 +/- 7.34 in control vs. 70.55 +/- 26.66 ml 100 g(-1) min(-1) in ischemic group; p < 0.05). Respective mean blood volume in tumors (11.7 +/- 13.3, 12.7 +/- 14.0, and 13.3 +/- 14.5 microl g(-1)) from ischemic-PBS, nonischemic-bradykinin, and ischemic-bradykinin groups, respectively, was not significantly different; mean blood volume in normal brain (3.7, 3.1 and 3.8 microl g(-1)) was not significantly different among these groups either. Intracarotid infusion of bradykinin following repeated ischemia significantly increased mean Ki, as compared to bradykinin infusion in nonischemic controls, in both the tumor center (36.60 +/- 8.4 vs. 22.90 +/- 4.61 microl g(-1) min(-1), p < 0.05) and in tumor periphery (17.70 +/- 5.93 vs. 8.50 +/- 4.42 microl g(-1) min(-1), p < 0.05). Mean Ki values for tumor center and tumor periphery of ischemic rats receiving intracarotid bradykinin were 3-fold greater than those of nonischemic rats infused with PBS. Immunohistochemical and Western blot analyses showed that repeated, short-term ischemia significantly increased the levels of bNOS in tumor cells and eNOS in tumor capillaries, but neither induced iNOS nor affected B2 receptor levels in tumor cells in vivo, as compared with nonischemic controls. Taken together, these results demonstrate for the first time that repeated, short-term ischemia augments bradykinin-mediated opening of the BTB. We conclude that the elevated intratumoral levels of bNOS and eNOS may 'prime' the NO generating capacity of tumor cells. Consequently, increased de novo synthesis and a correspondingly elevated concentration of NO within the tumor, therefore, may be one mechanistic explanation for the significantly increased, bradykinin-mediated BTB opening under ischemic conditions, reported here.

Animals↗
PubMed2001

Effect of whole-body x-irradiation on antigen-induced airway response in sensitized guinea pigs.

The objectives of this study were to test the hypothesis that x-irradiation inhibits the late asthmatic response (LAR) without influencing the early asthmatic response (EAR) and to examine the mechanism of the inhibitory effect. Twenty sensitized guinea pigs were irradiated at a dose of 8 Gy. The next day, one-half of the animals were injected intravenously with spleen cells (2 x 10(8)) collected from unirradiated sensitized guinea pigs, whilst the other half were injected with vehicle only. Ten additional unirradiated sensitized guinea pigs also received vehicle only. Antigen inhalation challenge took place two days later. Pulmonary resistance was measured for 6 h after antigen exposure, and bronchoalveolar lavage and lung fixation were then undertaken. The area under the percentage pulmonary resistance curve 2-6 h after allergen inhalation was used for analysis of the LAR, while the maximal percentage change in pulmonary resistance was used for analysis of the EAR. Irradiation abolished the LAR (364.4+/-49.4 versus 62.8+/-10.4) without inhibiting the EAR (229.3+/-27.2 versus 278.7+/-40.2) and significantly inhibited the accumulation of eosinophils and lymphocytes in the airways. Transfer of spleen cells restored the LAR (334.4+/-66.8) and the recruitment of cells to the levels seen in unirradiated sensitized guinea pigs. In addition, transfer of only CD4+ T-lymphocytes separated from the spleen cells restored the LAR (439.4+/-62.1) and the cell infiltration into the airways. These inhibitory effects of x-irradiation were due to decreases in numbers of CD4+ T-lymphocytes.

Airway Resistance↗
PubMed2001

The role of phosphatidylinositol 3-kinase and the mitogen-activated protein kinases in insulin-like growth factor-I-mediated effects in vascular endothelial cells.

Despite an improved understanding of the molecular mechanisms of insulin-like growth factor-I (IGF-I) signaling and the recognition that IGF-I mediates many effects in endothelial cells, some of which may be important for atherosclerosis, little is known about the signal transduction pathways that mediate the effects of IGF-I in endothelial cells. To that end, we examined the signaling pathways activated by IGF-I in endothelial cells and their contribution to IGF-I-stimulated endothelial cell migration and nuclear factor (NF)-kappaB-dependent transcription. Treatment of bovine pulmonary artery endothelial cells (PAEC) with IGF-I activated the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1/2 and ERK5. In contrast, IGF-I had no effect on either c-Jun amino-terminal kinase or p38 kinase activity. IGF-I also activated phosphatidylinositol (PI) 3-kinase, as reflected by increased phosphorylation of AKT: There was no evidence of cross-talk between the ERK and PI 3-kinase pathways in PAEC. In PAEC transiently transfected with pTK81-NFkappaB-Luc, which contained four copies of the NF-kappaB DNA binding site 5' to a minimal promoter and the luciferase gene, treatment with 50 ng/ml IGF-I increased luciferase activity 1.8-fold. Inhibition of ERK activity using PD98059 and PI 3-kinase activity with LY 294002 abrogated the induction of NF-kappaB-dependent transcription by IGF-I, suggesting that both pathways contribute to the effect of IGF-I on NF-kappaBdependent transcription. In contrast to the effect of tumor necrosis factor-alpha on NF-kappaB activation, Western blot analyses demonstrated that IGF-I had no effect on IkappaB phosphorylation and degradation or nuclear translocation and DNA binding of NF-kappaB. These data suggest a direct of effect of IGF-I on nuclear NF-kappaB. IGF-I also increased endothelial cell migration approximately 2-fold, as demonstrated using a Boyden chamber apparatus. IGF-I-induced endothelial cell migration was inhibited, in part, by LY 294002 but not PD98059. Together, these studies demonstrate that IGF-I activates multiple signaling pathways in endothelial cells with little evidence for cross-talk between the pathways. Moreover, these pathways appear to mediate both overlapping and distinct effects in that activation of both PI 3-kinase and the ERKs contributed to the stimulation of NF-kappaB-dependent transcription by IGF-I, whereas only PI 3-kinase mediated IGF-I-stimulated endothelial cell migration.

Animals↗
PubMed2001

Jing: a downstream target of slbo required for developmental control of border cell migration.

Epithelial to mesenchymal transitions and cell migration are important features of embryonic development and tumor metastasis. We are employing a systematic genetic approach to study the border cells in the Drosophila ovary, as a simple model for these cellular behaviors. Previously we found that expression of the basic-region/leucine zipper transcription factor, C/EBP, is required for the border cells to initiate their migration. Here we report the identification of a second nuclear factor, named JING (which means 'still'), that is required for initiation of border cell migration. The jing locus was identified in a screen for mutations that cause border cell migration defects in mosaic clones. The jing mutant phenotype resembles that of slbo mutations, which disrupt the Drosophila C/EBP gene, but is distinct from other classes of border cell migration mutants. Expression of a jing-lacZ reporter in border cells requires C/EBP. Moreover, expression of jing from a heat-inducible promoter rescues the border cell migration defects of hypomorphic slbo mutants. The JING protein is most closely related to a mouse protein, AEBP2, which was identified on the basis of its ability to bind a small regulatory sequence within the adipocyte AP2 gene to which mammalian C/EBP also binds. We propose that the need to coordinate cell differentiation with nutritional status may be the link between mammalian adipocytes and Drosophila border cells that led to the conservation of C/EBP and AEBP2.

Adipocytes↗
PubMed2001

Role of hypertension, dyslipidemia and diabetes mellitus in the development of coronary atherosclerosis in Japan.

The present study evaluated the effect of hypertension (HT), dyslipidemia and diabetes mellitus (DM) on the development of coronary atherosclerosis in the Japanese population, using a cross-sectional study of 433 patients (254 men and 179 women) aged 30 years or older who underwent coronary angiography for suspected or known coronary heart disease angina at 5 cardiology departments in the Fukuoka area between September 1996 and August 1997. Patients with a disease duration of 6 months or more were excluded. The main outcome measure was angiographically defined coronary artery stenosis and was found to a significant degree in 146 patients (33.7%). HT, DM, low levels of high-density lipoprotein cholesterol (HDL-C) and hypertriglyceridemia remained as significant coronary artery disease (CAD) risk factors even after controlling for age, sex, hospital, smoking, alcohol use, body mass index and leisure time physical activity. However, hypercholesterolemia was not a significant risk factor after adjusting for these variables. After controlling for these variables, DM, low HDL-C and hypertriglyceridemia were significant CAD risk factors for men, but only DM was a significant CAD risk factor in women. These results indicate that in Japan DM, low HDL-C and hypertriglyceridemia may be more important CAD risk factors than hypercholesterolemia.

Adult↗
PubMed2001

A-6G variant of the angiotensinogen gene and essential hypertension in Han, Tibetan, and Yi populations.

To investigate the relationship between the A-6G variant in the promoter of the angiotensinogen gene and essential hypertension in Han, Tibetan, and Yi populations. All patients with essential hypertension were selected by WHO criteria. And the polymorphism of the A-6G variant was determined by PCR/RFLP. The data were analyzed by t test and chi2 test. There was no significant difference in the genotype or allele frequencies between normotensives and hypertensives in the Han, Tibetan, and Yi populations, respectively. However, when the subjects were divided into male and female subgroups, the genotype distributions among hypertensives and normotensives of the Tibetan female group were as follows: AA, 37% vs. 48%; AG, 52% vs. 48%; GG, 11% vs. 4%, respectively and the frequency of the G allele was significantly higher in hypertensives than in normotensives in the Tibetan female group (0.37 vs. 0.28, chi2=4.25, p<0.05). In addition, we observed that there was a significant difference between the Han and Tibetan normotensive groups in the distributions of the allele and genotype frequencies of the A-6G variant. The frequency of the G allele was 0.29 and 0.17 in the Tibetan normotensive and Han groups, respectively (p<0.001). The G allele of the A-6G variant was associated with hypertension in the Tibetan females, but not in the Yi or Han females. And we confirmed that there was a significant difference in the prevalence of the allele frequencies of the A-6G variant between the Han and Tibetan normotensive groups.

Adult↗
PubMed2001

The effects of cardiac myocytes on interstitial fibroblasts in toxic iron overload.

Iron deposits preferentially in myocytes in mixed cultures of cardiac myocytes and nonmyocytic fibroblasts. In vivo, iron overload is associated with cardiac fibrosis. Therefore, we examined whether iron loading of cardiac myocytes in culture could trigger a response in nonmyocytes characteristic of a fibrogenic phenotype. We found that the nonmyocytes adopted a myofibroblast phenotype in culture. The rate of DNA synthesis (measured by [3H]thymidine incorporation) by the nonmyocytes was decreased by the myocyte-conditioned medium, compared to that of the unconditioned medium, and this activity was retained in <10-kDa fractions. The rate was partially restored when the medium was obtained from iron-loaded myocytes, and in this medium, the <10-kDa fraction was even more effective in reversing the suppression of proliferation. This suppression suggests a decreased secretion of a growth inhibitory substance in the iron-loaded myocytes, and this effect was partially reversed when the iron-loaded cells were treated with the iron chelator, deferoxamine. This indicates that cardiac myocytes may play a paracrine role in suppressing the proliferation of myofibroblasts that is partially overcome when the myocytes are iron overloaded. The myocyte-conditioned medium also affects the myofibroblast phenotype, increasing the cells' fibronectin mRNA content and decreasing alpha-smooth-muscle actin mRNA. The myocyte-conditioned medium increases transforming growth factor-beta (TGF-beta) secretion by myofibroblasts, but the TGF-beta content of the conditioned medium was found to play, at most, a minor role in determining the response of the myofibroblast.

Animals↗
PubMed2001

Administration of unmodified prolactin (U-PRL) and a molecular mimic of phosphorylated prolactin (PP-PRL) during rat pregnancy provides evidence that the U-PRL:PP-PRL ratio is crucial to the normal development of pup tissues.

During rat pregnancy initial high concentrations of prolactin (PRL) decline by about day 9, concomitant with an increase in the ratio of unmodified to phosphorylated PRL. The physiological significance of both the decline in total PRL and the change in ratio of the two PRLs is unknown. To test the importance of each, either unmodified PRL (U-PRL) or a molecular mimic of phosphorylated PRL (PP-PRL) were continuously administered to rats throughout pregnancy. A dose of 6 microg/24 h resulted in circulating concentrations of 50 ng/ml of each administered PRL and had little effect on the pregnancy itself. After birth, pups were killed and various tissues examined. In the pup lungs, exposure to additional PP-PRL caused a reduction in epithelial integrity and an increase in apoptosis, whereas exposure to additional U-PRL had beneficial, anti-apoptotic effects. In the heart, PP-PRL caused an apparent developmental delay, whereas U-PRL promoted tissue compaction. In the blood, U-PRL increased the number of mature red blood cells at the expense of white blood cell production. Within the white blood cell population, myelopoiesis was favored at the expense of lymphopoiesis. PP-PRL, in contrast, had a less dramatic influence on the hematopoietic compartment by promoting red blood cell maturation and granulocyte production. In the thymus, exposure to PP-PRL caused accumulation of apoptotic thymocytes in enlarged glands, whereas exposure to U-PRL resulted in smaller thymi. In the spleen, exposure to U-PRL increased cellularity, with the majority of cells belonging to the erythroid series - a finding consistent with increased red blood cells in the circulation. Exposure to PP-PRL was without discernible effect. In all of these tissues, the contrasting effects of the two PRLs indicate that the absolute concentration of PRL is not crucial, but that the ratio of U-PRL to PP-PRL has a profound effect on tissue development. In brown fat, both PRL preparations decreased the number of lipid droplets. This result is therefore probably a consequence of the increase in total PRL. The results of this study attest to the importance of the U-PRL:PP-PRL ratio normally present during pregnancy and have provided clues as to the possible pathogenesis of a variety of neonatal problems.

Animals↗