Endothelin as a natriuretic hormone: the case for a paracrine action mediated by nitric oxide.
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Animals↗
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Arterial gene transfer of acidic fibroblast growth factor for therapeutic angiogenesis in vivo: critical role of secretion signal in use of naked DNA.
OBJECTIVE: Previous studies have demonstrated that arterial gene transfer of naked DNA encoding for a secreted protein may permit modulation of the host phenotype despite a low transfection efficiency. Acidic fibroblast growth factor (aFGF) is an angiogenic growth factor, but is not secreted by intact cells. In the current study, we investigated the hypothesis that addition of a hydrophobic leader sequence to achieve active secretion of the gene product would permit therapeutic angiogenesis following arterial gene transfer of naked DNA encoding for aFGF. METHODS: Ten days following surgical induction of unilateral hindlimb ischemia, New Zealand white rabbits were randomized to intra-arterial gene transfer with one of three plasmids: p267 (encoding non-secreted aFGF, n = 10), pMJ35 (encoding secreted aFGF) (n = 10), or 500 micrograms of pGSVLacZ (control, n = 10) (500 micrograms each). All animals were studied at 30 days post-gene transfer for evidence of therapeutic angiogenesis. RESULTS: pMJ35 transfectants had more angiographically visible collaterals (angiographic score = 0.76 +/- 0.02) than either p267 (0.55 +/- 0.02, p < 0.01) or LacZ (0.47 +/- 0.02, p < 0.001). Limb blood pressure ratio for pMJ35 was 0.88 +/- 0.02 vs. 0.68 +/- 0.04 for p267 (p < 0.01) and 0.57 +/- 0.04 for LacZ (p < 0.001). Vascular resistance was significantly lower in the pMJ35 group, compared with that in pGSVLacZ group, both in resting state (3.2 +/- 0.4 vs. 7.4 +/- 1.4 respectively, p < 0.05) and after the administration of nitroprusside. Capillary density (per mm2) was also superior in pMJ35 group (274 +/- 10) vs. p267 (204 +/- 9, p < 0.01) and LacZ (177 +/- 6, p < 0.001). CONCLUSION: The paracrine effects of a secreted gene product may obviate the need for adjunctive vectors in strategies of arterial gene therapy.
Analysis of Variance↗
Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from fibroblasts.
OBJECTIVE: We sought to determine whether angiotensin II (Ang II) promotes hypertrophy of cardiac directly or via paracrine mechanisms mediated by cardiac fibroblasts. METHODS: We studied neonatal rat cardiac myocytes and fibroblasts in culture as a model system. Paracrine effects of Ang II were identified using conditioned medium and co-culture experiments. RESULTS: Ang II type 1 (AT1) receptors responsible for myocyte growth localized to fibroblasts in radioligand binding, emulsion autoradiography, Western analysis, and immunofluorescence staining experiments. The bulk of AT1 receptor binding in myocyte cultures (1343 +/- 472 sites/cell) was to Ang II receptors on contaminating fibroblasts (9747 +/- 2126 sites/cell). Ang II induced significant paracrine trophic effects on myocytes in conditioned medium (40% increase in protein synthesis over control) and co-culture (4-fold increase over control) experiments. TGF-beta 1 and endothelin-1 were paracrine mediators of hypertrophy in neutralization experiments. CONCLUSIONS: Ang II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from cardiac fibroblasts in a neonatal rat cell culture model.
Angiotensin II↗
Potential paracrine role of the pericardium in the regulation of cardiac function.
OBJECTIVE: Both coronary and endocardial endothelium regulate cardiac contractile function via paracrine pathways. We investigated whether pericardial fluid (PF) and pericardial mesothelial cells (PMC) could exert a similar paracrine action. METHODS: Both PF and PMC were extracted from sheep pericardial space. Endothelin-1, prostaglandins and atrial natriuretic factor were measured in PF in vivo. In the other hand, PMC were grown on T-75 flasks and microcarrier beads to investigate endothelin-1, nitric oxide and prostaglandin pathways in vitro. In addition, effects of PF and PMC effluent were tested on adult rat cardiac myocyte contraction in vitro. RESULTS: In vitro, cultured PMC expressed endothelin-1 mRNA but not the endothelial nitric oxide synthase III, and released endothelin-1 and prostaglandins. Both PF and cultured PMC superfusate induced a potent, rapidly reversible decrease in the shortening of isolated rat cardiac myocytes. This effect was not associated with changes in intracellular calcium. In vivo, prostaglandins, atrial natriuretic factor and endothelin were present in PF. A greater concentration of atrial natriuretic factor was present in PF than in serum, suggesting molecular diffusion from the myocardium to PF. Preliminary results show that the instillation of vasoactive agents into the pericardial space of dogs rapidly alter coronary and systemic vascular tone, consistent with a molecular diffusion of these substances from PF into the myocardium and circulation. CONCLUSIONS: In addition to its mechanical role, the pericardium may contribute to the integration and the regulation of cardiovascular function via a paracrine mechanism.
Animals↗
Paracrine hypertrophic factors from cardiac non-myocyte cells downregulate the transient outward current density and Kv4.2 K+ channel expression in cultured rat cardiomyocytes.
OBJECTIVES: Cardiac hypertrophy is characterized by a prolongation of action potential duration (APD) and a reduction of outward K+ currents, primarily the transient outward current (Ito). Since the interaction between cardiac non-myocyte cells (NMCs) and cardiomyocytes (MCs) plays a critical role during the process of myocardial hypertrophy, in the present study, we investigated the effects of NMCs on cell growth and K+ channel expression in cultured newborn rat ventricular cells. METHODS: Single MCs were isolated from day-old Wistar rat ventricles and cultured for a period of five days. The effects of NMCs were examined by MC-NMC co-culture or incubating pure MCs in NMC-conditioned growth medium (NCGM). Whole-cell voltage-clamp recording and Western blot analysis using a polyclonal antibody against rat Kv4.2 channel protein were performed. RESULTS: A marked increase in surface area and total cell protein concentration of MCs was observed in the MC-NMC co-culture. In the pure MC culture, this hypertrophic effect could be mimicked by a 72-h addition of NCGM, with a significant prolongation of APD25 (APD at 25% repolarization) and a 42% decrease in Ito density (at +30 mV). The rates of inactivation and recovery from inactivation of Ito were unchanged. In the NCGM-treated MC culture, Western blots of MC proteins also showed a 36% reduction of the Kv4.2 K+ channel protein level. In addition, the NCGM-induced MC hypertrophy was partially inhibited by anti-insulin-like growth factor-1 (IGF-1) antibody, while it revealed no effects on Ito density and Kv4.2 channel expression. CONCLUSIONS: These findings first demonstrate that some paracrine hypertrophic factors released from cardiac NMCs, although unidentified, downregulate cardiac K+ channel expression.
Animals↗
Impaired paracrine effect of endothelin-1 on vascular smooth muscle in streptozotocin-diabetic rats.
OBJECTIVE: This study was to examine the effect of streptozotocin-induced diabetes on endothelin-1 and its receptors in the mesenteric artery and in the thoracic aorta. METHODS: Diabetes was induced in SD rats by streptozotocin. Insulin was given subcutaneously. Endothelin-1 levels in the plasma, thoracic aorta and mesenteric artery were measured using radioimmunoassay. The Bmax and Kd values of endothelin-1 receptors in the mesenteric artery and in the thoracic aorta were analyzed using Scatchard plot analysis. Preproendothelin mRNA levels were examined using RT-PCR. RESULTS: Endothelin-1 levels in the mesenteric artery (83.6 +/- 6.9 pg/mg protein) and in the thoracic aorta (73.9 +/- 8.2 pg/mg protein) increased in 2 week diabetic rats compared with both control (51.8 +/- 5.3, 46.3 +/- 5.9 pg/mg protein) and insulin treated rats (65.6 +/- 8.1, 48.1 +/- 4.2 pg/mg protein) but not in 4 week diabetic rats. There was no change in plasma endothelin-1 levels in these diabetic rats. The RT-PCR results indicated that preproendothelin mRNA levels in the mesenteric artery (0.38 +/- 0.02 vs 0.52 +/- 0.05 units) and in the thoracic aorta (0.45 +/- 0.06 vs 0.62 +/- 0.03 units) decreased in 4 week diabetic rats but not in 2 week diabetic rats. A significant increase in Kd and Bmax of endothelin receptors in the mesenteric artery and in the thoracic aorta was observed in both 2 week (about 70%) and 4 week (80-85%) diabetic rats. Insulin replacement reversed the effects of diabetes on endothelin-1 peptide contents, preproendothelin mRNA levels and the binding activity in the blood vessels. CONCLUSION: Increased endothelin peptide content with no change in mRNA or decreased mRNA levels with no change in peptide content together with increased receptor binding sites and affinities might imply a decrease in endothelin release and therefore an impaired paracrine effect of endothelin on vascular smooth muscles in these STZ-diabetic rats.
Analysis of Variance↗
Role of nitric oxide in the neural control of cardiovascular function.
The discovery in 1990 that nitric oxide (NO) acts as a neuromodulator within the central and peripheral nervous system triggered intensive research which considerably extended our understanding how this factor regulates cardiovascular functions. In addition to its direct effects on blood vessels NO has additional targets at all levels of the neural control of circulation. When not scavenged by hemoglobin, NO is relatively stable and diffuses over large distances (> 500 microns) so that one NO-producing cell can influence several thousands of adjacent cells in vivo. In different brain regions, NO and its metabolites have excitatory as well as inhibitory effects. The modulation of autonomic functions by these factors is therefore highly complex and often variable between the different levels from the brain to postganglionic nerve endings. This review is focused on the available evidence derived from animal studies and will summarize the current discussion about (i) the modulation of the generation of sympathetic and parasympathetic activities within the brain stem by NO; (ii) the actions of NO on cardiovascular reflexes and (iii) the role of NO as a modulator of autonomic functions within the target organs. Finally, the available evidence from human studies and some pathophysiological implications of altered NO-mediated modulation of the neural control of circulation will be discussed.
Animals↗
Altered paracrine effect of endothelin in blood vessels of the hyperinsulinemic, insulin resistant obese Zucker rat.
OBJECTIVE: Earlier, we reported that high insulin incubation in vitro leads to increased ETA receptor expression in cultured rat aortic smooth muscle cells (Diabetes 1998, 47: 934-944). Our later observation of enhanced endothelin-1 evoked vasoconstriction in aorta from the hyperinsulinemic obese Zucker rat indicated that this interaction might also be relevant in vivo. To further examine the relationship between insulinemia and endothelin, we characterized endothelin receptor expression and endothelin-1 peptide levels in vascular tissues and plasma from young and old obese Zucker rats. METHODS: 12 and 40-week-old Zucker obese and lean rats were used. Plasma endothelin-1 levels and endothelin-1 peptide content in the mesenteric artery and in the thoracic aorta were examined by radioimmunoassay. Messenger RNA levels of endothelin-1 peptide and ETA and ETB receptors were examined in the aortic and mesenteric vessels using RT-PCR. RESULTS: Obese rats from both age groups had significantly higher plasma levels of insulin (4-10 fold), total cholesterol (2-3 fold), triglycerides (10-fold), and glucose (approximately 1.5 fold) than their lean counterparts. There was a trend toward worsening lipoproteinemia and glycemia, but improved insulinemia with age in the obese rats. In association with these changes, obese rats exhibited attenuated endothelin-1 peptide and preproET-1 mRNA levels, but conversely elevated ETA and ETB receptor mRNA levels in both aortic and mesenteric vessels. CONCLUSION: These data suggest that vascular tissue from the metabolically dysregulated obese Zucker rat exhibits attenuated endothelin-1 peptide production and elevated endothelin receptor levels. Since elevated insulin levels have been linked to increased endothelin receptor expression, it is plausible that hyperinsulinemia upregulates endothelin receptors contributing to elevated vasoconstrictor responses to endothelin-1 in this model of obesity and hypertension.
Animals↗
Paracrine regulation of talin mRNA expression by androgen in human prostate.
Androgens are essential for normal prostate physiology and are intimately associated with the growth and progression of prostate cancer. However, few androgen regulated genes in the prostate have been identified. Using the mRNA differential display technique a 164-bp cDNA fragment was identified as being androgen regulated in the human prostate. Nucleotide sequence analysis of this fragment revealed 84% homology with the gene encoding the cytoskeletal protein talin. Confirmation of the androgen regulation of this gene was carried out using Northern analysis. Primary prostatic stromal cells treated with conditioned medium (CM) from androgen-treated primary prostatic epithelial cells showed an approximate 2-fold reduction in talin mRNA levels compared with stromal cells treated with CM from epithelial cells not exposed to androgens. Expression of talin mRNA in human prostatic tissue was confirmed by in situ hybridisation. The highest levels of expression were present in the epithelial cells, with lower levels of expression in the stroma. Thus, androgen regulation of talin expression may play a role in normal and/or aberrant growth and development of the prostate.
Androgens↗
Number, distribution pattern, and identification of macrophages in the testes of infertile men.
OBJECTIVE: To investigate the number, location, and secretory products of macrophages in human testes showing normal and abnormal spermatogenesis. DESIGN: Evaluation of testicular biopsies with the use of immunohistochemistry, laser capture microdissection, and reverse transcriptase polymerase chain reaction. SETTING: University research and clinical institutes. PATIENT(S): Infertile men with germ cell arrest (n = 10), Sertoli cell only (n = 8), or mixed atrophy (n = 7) syndromes, and with cases of idiopathic infertility showing normal spermatogenesis (n = 8). INTERVENTION(S): Diagnostic testicular biopsy was performed on participants. MAIN OUTCOME MEASURE(S): We recorded the location, number, distribution, and cytokine expression of human testicular macrophages. RESULT(S): CD68-positive macrophages were found in the testes of all groups analyzed. These macrophages expressed the genes for interleukin 1 and tumor necrosis factor-alpha, and were located in the interstitium, tubular wall, and tubular lumen. In Sertoli cell only and germ cell arrest syndromes, the overall macrophage number was increased over twofold. In all pathologic states, there was a significant shift of these cells from the interstitium to the tubules. CONCLUSION(S): Our study suggests that increased numbers of CD68-positive macrophages directly (via phagocytosis) or indirectly (via paracrine actions exerted through their secretory products) are involved in the regulation of steroidogenesis, Sertoli cell activity, germ cell survival, and, in consequence, in the pathogenesis or maintenance of infertility states in the human testes.
Adult↗
Detection of thioredoxin in human serum and biological samples using a sensitive sandwich ELISA with digoxigenin-labeled antibody.
Thioredoxin is a low molecular weight, redox active protein important in cellular proliferation, signal transduction and antioxidant function. Thioredoxin is secreted by normal as well as neoplastic cells and is potentially involved in paracrine cell communication as suggested by its co-cytokine activity. Thus, the thioredoxin level in biological fluids, cells and tissue homogenates could be an important indicator of physiological or pathophysiological conditions. Hence, an accurate and sensitive measurement is of paramount importance in studies involving thioredoxin. We present here an ultrasensitive enzyme linked immuno-absorbent assay (ELISA) for human thioredoxin using digoxigenin-labelled goat polyclonal anti-human thioredoxin. The assay could detect a minimum level of 15 pg/ml thioredoxin in human serum, cell culture media, and in cell and tissue samples. The assay was optimized for concentration of both antibodies, blocking agent, plates, incubation time and reaction volumes. Excellent linearity and reproducibility were obtained. The assay was applied to different baboon tissues and human serum samples. The intrassay coefficient of variation (CV) was between 6.0 to 14 and the interassay CV was from 1.6 to 11.1. Excellent parallelism of standards with serum samples, tissue homogenates or cell lysates was obtained. More than 90% recovery of human thioredoxin was observed in 10% human serum. The assay is easy to use, rapid, reproducible, but above all it is a quantitative, specific and sensitive way to measure thioredoxin in a variety of biological specimens.
Animals↗
Role of progesterone on peri-implantation stage endometrium-embryo interaction in the primate.
Progesterone secretion during the luteal phase influences oviductal and endometrial functions which are essential for embryo viability and implantation in a number of species including primates. Luteal phase estrogen is not essential for progesterone-dependent endometrial receptivity towards implantation and pregnancy in the rhesus monkey and in the human. However, synchronous development of embryo and endometrium is an essential prerequisite for evolutive implantation. Progesterone helps to maintain synchronous development of preimplantation embryo through its action on maternal uterus. The anti-nidatory action of mifepristone, a potent progesterone receptor modulator (PRM) with pronounced antiprogestagenic activity, is known to be associated with desynchronization of endometrium along with repression of glandular secretory differentiation and vascular maturation. Thus, it is likely that early luteal phase administration of mifepristone affects paracrine action of the secretory stage endometrium on the preimplantation stage embryo, and thereby inhibits embryonic development and viability. We shall examine this hypothesis using the rhesus monkey as a primate model.
Animals↗
Clopidogrel inhibits platelet adhesion and platelet-dependent mitogenesis in vascular smooth muscle cells.
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Adenosine Diphosphate↗
Proadrenomedullin-derived peptides in the paracrine control of the hypothalamo-pituitary-adrenal axis.
Adrenomedullin (ADM) and proadrenomedullin N-terminal 20 peptide (PAMP) are widely distributed in various body tissues and organs, including the hypothalamo-pituitary-adrenal (HPA) axis. ADM and PAMP inhibit in vitro release of ACTH from pituitary corticotropes, and findings suggest that this effect may become relevant when an exceedingly high ACTH secretion must be counteracted. ADM directly supresses angiotensin-II- and K+-stimulated aldosterone secretion from ZG cells, acting through calcitonin gene-related peptide (CGRP) type 1 ADM(22-52)-sensitive receptors, the activation of which is likely to impair Ca2+ influx. In contrast, ADM stimulates medullary chromaffin cells to release catecholamines, which in turn enhance aldosterone secretion acting in a paracrine manner. Also this effect of ADM occurs via CGRP1 receptors, which are coupled with the adenylate cyclase-dependent cascade. There is indication that in vivo these two opposite effects of ADM on ZG may interact with each other when normal aldosterone secretion has to be restored. ADM exerts a mitogenic effect on rat ZG, acting via CGRP1 receptors that activate the tyrosine kinase-dependent mitogen-activated protein kinase cascade. These findings, along with the demonstration of a high level of ADM gene expression in adrenocortical adenomas and carcinomas, may suggest a role for ADM as adrenocortical growth stimulator and tumor promoter. PAMP, like ADM, suppresses aldosterone response of ZG cells to Ca2+-dependent agonists, but, in contrast with ADM, it inhibits catecholamine release by adrenal medulla. Both effects of PAMP are mediated by PAMP(12-20)-sensitive receptors, whose signaling mechanism is likely to involve the blockade of voltage-gated Ca2+ channels. The concentrations attained by ADM and PAMP in the blood rule out the possibility that they act as true circulating hormones. Conversely, their content in the hypothalamo-pituitary complex and adrenal gland is consistent with a paracrine mechanism of action, which may play an important role in pathophysiological conditions where the function of the HPA axis has to be reset.
Adrenal Glands↗
Fibroblast growth factor 2: its structure and property, paracrine function, tumor angiogenesis, and prostate-related mitogenic and oncogenic functions.
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Adenocarcinoma↗
MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis.
The matrix metalloproteinase MMP-9/gelatinase B is upregulated in angiogenic dysplasias and invasive cancers of the epidermis in a mouse model of multi-stage tumorigenesis elicited by HPV16 oncogenes. Transgenic mice lacking MMP-9 show reduced keratinocyte hyperproliferation at all neoplastic stages and a decreased incidence of invasive tumors. Yet those carcinomas that do arise in the absence of MMP-9 exhibit a greater loss of keratinocyte differentiation, indicative of a more aggressive and higher grade tumor. Notably, MMP-9 is predominantly expressed in neutrophils, macrophages, and mast cells, rather than in oncogene-positive neoplastic cells. Chimeric mice expressing MMP-9 only in cells of hematopoietic origin, produced by bone marrow transplantation, reconstitute the MMP-9-dependent contributions to squamous carcinogenesis. Thus, inflammatory cells can be coconspirators in carcinogenesis.
Animals↗
Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.
Oct4 is a mammalian POU transcription factor expressed by early embryo cells and germ cells. We report that the activity of Oct4 is essential for the identity of the pluripotential founder cell population in the mammalian embryo. Oct4-deficient embryos develop to the blastocyst stage, but the inner cell mass cells are not pluripotent. Instead, they are restricted to differentiation along the extraembryonic trophoblast lineage. Furthermore, in the absence of a true inner cell mass, trophoblast proliferation is not maintained in Oct4-/- embryos. Expansion of trophoblast precursors is restored, however, by an Oct4 target gene product, fibroblast growth factor-4. Therefore, Oct4 also determines paracrine growth factor signaling from stem cells to the trophectoderm.
Animals↗