Biomedical subjects

William R Gower

Publications and source records attributed to William R Gower.

13 recordsLinked to original sources

PubMed2006

Identification, regulation and anti-proliferative role of the NPR-C receptor in gastric epithelial cells.

Evidence suggests that functional atrial natriuretic peptide (ANP) receptors occur in surface gastric mucosal epithelial cells. To evaluate functional aspects of ANP in a model of these cells we examined the expression of natriuretic peptide receptors (NPR) subtypes A and C in the non-transformed rat gastric mucosal epithelial cell line RGM1. Transcripts for NPR-A and NPR-C were detected in RGM1 cells by RT-PCR. However, only NPR-C protein was detected by Western blot and immunohistochemical analyses. Specific saturable binding of (125)I-ANP to RGM1 cells revealed a single class of high affinity binding sites (K (d) = 208 +/- 71pM, B (max) = 110,000 +/- 14,000 sites/cell, Hill coefficient = 0.97 +/- 0.05). ANP (IC(50) 130 +/- 47pM), BNP (IC(50) 716 +/- 26 pM), CNP (IC(50) 356 +/- 85pM) and C-ANP (IC(50) 134 +/- 13pM), a specific ligand for NPR-C, effectively displaced (125)I-ANP binding. Cross-linking of (125)I-ANP to cells labeled predominantly a protein of 66,000 Da. These data suggest that (125)I-ANP binding was primarily to NPR-C. ANP and C-ANP inhibited forskolin- and prostaglandin E(2) (PGE(2))-stimulated cAMP in a PTx-sensitive fashion. PGE(2), transforming growth factor-+/-1 (TGF-+/-1), forskolin, 8-bromo-cyclic AMP, and phorbol-12-myristate-13-acetate (PMA) caused a dose-dependent decrease in specific (125)I-ANP binding, whereas epidermal growth factor (EGF), 8-bromo-cyclic GMP and 4+/--phorbol didecanoate had no effect. PGE(2), forskolin, TGF-+/-1 and PMA significantly decreased (125)I-ANP B (max) values, NPR-C protein and steady-state NPR-C transcript levels. H89, a protein kinase A inhibitor, blocked the reduction of NPR-C mRNA produced by both forskolin and PGE(2.) GF109203X, a protein kinase C inhibitor, abolished the PMA-induced decrease in NPR-C transcripts but only partially blocked that produced by TGF-+/-1. RGM1 cells exhibited a dose-dependent decrease in both DNA synthesis and cell proliferation when cultured in the presence of ANP or C-ANP. These findings indicate that RGM1 cells express functional NPR-C receptors that can influence RGM1 cell proliferation and are down-regulated by PGE(2) and TGF-+/-1.

Adenylyl Cyclases↗

PubMed2006

Primary malignant tumors of the heart: four cardiovascular hormones decrease the number and DNA synthesis of human angiosarcoma cells.

BACKGROUND: A family of six cardiovascular hormones--atrial natriuretic peptide, brain natriuretic peptide, C-natriuretic peptide, long acting natriuretic peptide, vessel dilator and kaliuretic peptide--was investigated for the ability to decrease the number of human angiosarcoma cells. METHODS AND RESULTS: Within 24 h, vessel dilator, long acting natriuretic peptide, kaliuretic peptide, atrial natriuretic peptide and their intracellular mediator cyclic GMP decreased the number of angiosarcoma cells by 61, 30, 29, 36 and 32%, respectively, and DNA synthesis by 68-85%. Brain natriuretic peptide and C-natriuretic peptide had no effect(s). The natriuretic peptide receptor C was present. CONCLUSIONS: Four cardiovascular hormones decrease the number of angiosarcoma cells within 24 h via inhibition of DNA synthesis mediated in part by cyclic GMP.

Analysis of Variance↗

PubMed2006

Vessel dilator: most potent of the atrial natriuretic peptides in decreasing the number and DNA synthesis of human squamous lung cancer cells.

Within 24 h four peptide hormones, i.e. vessel dilator, long acting natriuretic peptide, kaliuretic peptide, and atrial natriuretic peptide and their intracellular mediator cyclic GMP decreased the number of human squamous lung cancer cells 51, 22, 25, 21, and 30%, respectively. There was not any proliferation in the 3 days following this decrease in cell number. Vessel dilator decreased DNA synthesis 85% in the squamous lung cancer cells. Thus, vessel dilator significantly decreased the number of human squamous lung cancer cells and their DNA synthesis, mediated in part by cyclic GMP, more than other peptide hormones.

Atrial Natriuretic Factor↗

PubMed2005

Immunocytochemical localization of atrial natriuretic peptide, vessel dilator, long-acting natriuretic peptide, and kaliuretic peptide in human pancreatic adenocarcinomas.

We recently found that four peptide hormones synthesized by the same gene completely inhibit the growth of human pancreatic adenocarcinomas in athymic mice. The present immunocytochemical investigation was designed to determine where in the adenocarcinomas these peptide hormones localize. Atrial natriuretic peptide, vessel dilator, long-acting natriuretic peptide, and kaliuretic peptide localized to the cytoplasm and nucleus of the human pancreatic adenocarcinomas, which is consistent with their ability to decrease DNA synthesis in the nucleus of this cancer. In this first investigation of where these peptide hormones with anticancer effects localize in any cancer, these peptide hormones also localized to the endothelium of capillaries and fibroblasts within these cancers. This is the first demonstration of growth-inhibiting peptide hormones localizing to the nucleus, where they inhibit DNA synthesis and may interact with growth-promoting hormones that localize there as the etiology of their ability to inhibit the growth of adenocarcinomas both in vitro and in vivo.

Adenocarcinoma↗

PubMed2005

Four peptides decrease human colon adenocarcinoma cell number and DNA synthesis via cyclic GMP.

BACKGROUND: Mortality from colon cancer is significant with an expected 30,350 colon cancer deaths in 2005 with current treatment(s). Long-acting natriuretic peptide, vessel dilator, kaliuretic peptide, and atrial natriuretic peptide have significant anticancer effects in breast and pancreatic adenocarcinomas. AIM OF STUDY: Whether these peptide hormones have anticancer effects in colon adenocarcinoma cells and whether these effects are specifically mediated by cyclic GMP has not been determined. METHODS: These peptide hormones were evaluated for anticancer effects in human colon adenocarcinoma cells and to determine whether their anticancer effects are specifically mediated by cyclic GMP. RESULTS: There was a 89-97% decrease (p <0.001 for each) in colon adenocarcinoma cells within 24 h with 1 mM of these peptide hormones. There was a significant (p <0.05) decrease in human colon cancer cell number with each 10-fold increase in concentration from 1 to 1,000 microM (i.e., 1 mM) of these four peptide hormones without any proliferation in the 3 d following this decrease. These same hormones decreased DNA synthesis 65-83% (p <0.001). Cyclic GMP antibody inhibited 75- 80% of these peptides' ability to decrease colon adenocarcinoma cell number and inhibited 92-96% of their DNA synthesis effects and 97% of cyclic GMP's effects. Western blots revealed that for the first time natriuretic peptide receptors (NPR) A and C were present in colon adenocarcinoma cells. CONCLUSIONS: Four peptide hormones eliminate up to 97% of colon cancer cells within 24 h with their DNA effects specifically mediated by cyclic GMP.

Adenocarcinoma↗

PubMed2004

Kupffer cell-derived Fas ligand plays a role in liver injury and hepatocyte death.

Liver injury is an important prognostic indicator during acute pancreatitis. The aim of this study was to determine the role of Fas ligand (FasL) in hepatocyte injury. Liver parenchymal enzymes were measured in cocultures of hepatocytes and Kupffer cells treated with elastase. FasL and FasL mRNA were measured in elastase-treated Kupffer cells. Hepatocytes were treated with FasL and their viability was assessed by monotetrazolium (MTT), apoptosis by flow cytometry, as well as caspase-3 and p38-mitogen-activated protein kinase (MAPK) by immunoblotting. Elastase increased aspartate aminotransferase and lactate dehydrogenase in cocultures of hepatocyte and Kupffer cells (P<0.040). Elastase increased FasL production from Kupffer cells (P=0.02) and upregulated FasL mRNA (FasL/beta-2 microglobulin (BMG): 0.23+/-0.03 vs. 0.11+/-0.003; P=0.04). FasL increased alanine aminotransferase and lactate dehydrogenase (P<0.03) and reduced hepatocyte viability by 45% (P=0.01). FasL increased the number of dually labeled cells with AnnexinV/7AAD (P=0.03) while upregulating cleavage of caspase-3 and the phosphorylation of p38-MAPK. FasL antibody attenuated the FasL-related increase in dually labeled cells (P=0.02), the cleavage of caspase-3, and phosphorylation of p38-MAPK. Pancreatic elastase upregulates FasL within Kupffer cells. FasL induces hepatocyte injury and death and upregulates p38-MAPK and caspase-3 within hepatocytes. The ability to manipulate interactions between Kupffer cells and hepatocytes may have important therapeutic implications.

Animals↗

PubMed2004

Natriuretic peptides and genesis of asthma: an emerging paradigm?

Exposure to allergens and infections contribute to early immune development. However, knowledge of the role of cellular metabolic, physiologic, and endocrinologic factors in controlling immune development and asthma is limited. Immune cells, including macrophages, dendritic cells, and T lymphocytes, express receptors for atrial natriuretic peptide (ANP) both in the fetal and neonatal lymphoid organs. ANP has garnered much attention for its cardiovascular effects, but its apparently significant role in the physiology and immunity of the lung has been underappreciated. Studies indicate that ANP also plays a significant role in shaping the early immune responses to environmental antigens. The C-terminal prohormone natriuretic peptide ANP (or NP(99-126)), which possesses bronchodilatory properties, is involved in polarizing dendritic cells to produce a T(H)2 response. Also, de novo overexpression of another pro-ANP peptide, NP(73-102), provides persistent bronchoprotection and induces significant anti-inflammatory activities in the lung epithelial cells. Thus natriuretic peptides appear to play a pivotal role in the genesis and control of asthma, and they might provide an important target to modulate allergen-induced immune responses in allergic patients.

Asthma↗

PubMed2004

Effects of cardiac hormones on arterial pressure and sodium excretion in NPRA knockout mice.

These studies were designed to determine if the atria contains natriuretic substances that act through a non-natriuretic peptide type A (NPRA) receptor mechanism. C57BL/6 mice, either wild-type NPRA++ (WT) or NPRA-- knockout (KO), were anesthetized with pentobarbital. Catheters were placed in the trachea, carotid artery, jugular vein, and bladder. Urine was collected for six 30-min periods. Both groups received an iv injection of 100 ng of rat atrial natriuretic peptide (rANP) in 200 microl of saline after the first period (30 mins) and 200 microl of rat atrial extract after the fourth period (120 mins). ANP injection increased urine flow (UF) to 2.7 +/- 0.5 microl/min in the WT versus 1.9 +/- 0.2 in KO. Extract increased UF to 7.9 +/- 1.5 microl/min in WT versus 2.7 +/- 0.4 in KO (P < 0.01). ANP increased sodium excretion (ENa) to 0.47 +/- 0.10 micromoles/min in WT versus 0.27 +/- 0.04 in KO (P < 0.05). Extract increased ENa to 1.44 +/- 0.47 micromoles/min in WT versus 0.26 +/- 0.06 in KO (P < 0.05). Extract decreased mean arterial pressure (MAP) to 62 +/- 3 mm Hg in the WT versus 81 +/- 5 in KO (P < 0.01). ENa and MAP responses to extract in KO were not different from responses to 200 microl of saline. A constant 150-min infusion of rat atrial extract increased urine flow by 3-fold and ENa by 5-fold (both P < 0.05) in the WT mice but had no significant effect in the KO mice. Thus, acute renal and MAP responses to atrial extracts require the NPRA receptor.

Animals↗

PubMed2003

Regulation of Kupffer cell TNF gene expression during experimental acute pancreatitis: the role of p38-MAPK, ERK1/2, SAPK/JNK, and NF-kappaB.

We have demonstrated that Kupffer cell-derived tumor necrosis factor (TNF) mediates pancreatitis-associated liver injury. The aim of this study was to determine the role of p38 mitogen-activated protein kinase (MAPK), extracellular stress-related kinase 1/2 (ERK1/2), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and nuclear factor-kappaB (NF-kappaB) in TNF gene expression within Kupffer cells. TNF and TNF-mRNA were measured in rat livers perfused with elastase. TNF, TNF-mRNA, NF-kappaB activation, and phosphorylated p38-MAPK, SAPK/JNK, and ERK1/2 were determined in Kupffer cells treated with elastase. Elastase increased TNF and upregulated TNF-mRNA in livers (P<0.03) and Kupffer cells (P<0.001). Phosphorylated p38-MAPK, SAPK/JNK, and ERK1/2 and activated NF-kappaB were detected in Kupffer cells at 7 minutes; at 60 minutes, TNF-mRNA peaked and NF-kappaB returned to baseline, whereas all three kinases remained activated. Gadolinium inhibited elastase-induced upregulation of TNF-mRNA (P < 0.001), TNF production (P<0.001), and attenuated SAPK/JNK, as well as ERK1/2, but not p38-MAPK. Both UO126 and SB203580 significantly inhibited elastase-induced upregulation of TNF-mRNA and TNF production (P<0.001), but only UO126 inhibited activation of NF-kappaB. It was concluded that pretranscriptional regulation of TNF gene expression in Kupffer cells follows an orderly activation of p38-MAPK, ERK1/2, and SAPK/JNK that may not converge on NF-kappaB. The seemingly limited duration of NF-kappaB activation may be important in "switching off" the cytokine cascade during acute pancreatitis.

Acute Disease↗

PubMed2003

Atrial natriuretic hormone prohormone gene expression in cardiac and extra-cardiac tissues of diabetic Goto-Kakizaki rats.

The present investigation was designed to determine if the mechanism for the increased atrial natriuretic peptides within the circulation of diabetic animals involves atrial natriuretic hormone prohormone (proANH) gene expression upregulation. The tissue specificity of this potential upregulation of the proANH gene was investigated in a spontaneous model of type 2 diabetes, i.e. the Goto-Kakizaki (GK) rat with comparison to age-matched non-diabetic Wistar rats from which the GK colony was originally derived. Reverse transcription-polymerase chain reaction revealed that proANH gene expression was increased 3.1-fold in the left heart ventricle, 5-fold in lung, 2-fold in kidney, 3-fold within mucosa and 1.8-fold within muscle of gastric antrum (p < 0.05 for each) of GK rats compared to Wistar rats. There was no significant increase in proANH gene expression in atria and right ventricle of the heart of GK rats compared to Wistars. These results indicate that steady-state ANH prohormone mRNA levels increase within the left ventricle and extracardiac tissues in type 2 diabetic animals. This enhanced gene expression is a functional increase with its expressed proteins (4 peptide hormones; ANPs) increasing 2-6 fold within the circulation of GKs. The greater increase in proANH messenger RNA in the extracardiac tissues compared to the amount of increase within the heart and the greater tissue mass of these combined extra cardiac tissues suggests the majority of the increase in ANPs within the circulation of diabetics is secondary to increased synthesis in extracardiac tissues. This also suggests that there is a systemic regulatory mechanism of proANH gene expression not only within the heart but also within the lung, gastrointestinal tract and kidney. Diabetes is the first disease in which there is more upregulation of ANH prohormone in extracardiac tissues compared to upregulation within the heart itself.

Animals↗

PubMed2003

Neutralization of proANP (1-30) exacerbates hypertension in the spontaneously hypertensive rat.

1. The aim of the present studies was to determine the role of proANP (1-30) in the regulation of arterial pressure. It was hypothesized that blocking endogenous proANP (1-30) would exacerbate the hypertension in susceptible animal models. 2. Pentobarbital-anaesthetized spontaneously hypertensive rats (SHR) were pretreated i.v. with 1.2 mL rabbit serum containing an antibody directed specifically against rat proANP (1-30) (SHR-AB group; n = 7) or an equal volume of normal rabbit serum as a control (SHR-NRS group; n = 5). 3. Following a 1 h equilibration period and two 30 min baseline periods, rats were volume expanded with 3 mL of 6% albumin in Krebs' solution and observed for an additional 3 h to determine the effects of the anti-proANP on arterial pressure. 4. Arterial pressure increased in both groups compared with their own baselines with volume expansion, but was significantly greater in the anti-proANP SHR group compared with the SHR-NRS group throughout the volume expansion period. A maximum difference of 21 mmHg between the anti-proANP SHR group and the NRS-SHR group was observed at 150 min of the study (183 +/- 5 vs 162 +/- 3 mmHg, respectively; P < 0.005. 5. These results suggest a protective role for proANP (1-30) in the SHR model of hypertension.

Animals↗

PubMed2003

Regulation of atrial natriuretic peptide secretion by cholinergic and PACAP neurons of the gastric antrum.

Atrial natriuretic peptide (ANP) released from enterochromaffin cells helps regulate antral somatostatin secretion, but the mechanisms regulating ANP secretion are not known. We superfused rat antral segments with selective neural agonists/antagonists to identify the neural pathways regulating ANP secretion. The nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) stimulated ANP secretion; the effect was abolished by hexamethonium but doubled by atropine. Atropine's effect implied that DMPP activated concomitantly cholinergic neurons that inhibit and noncholinergic neurons that stimulate ANP secretion, the latter effect predominating. Methacholine inhibited ANP secretion. Neither bombesin nor vasoactive intestinal polypeptide stimulated ANP secretion, whereas pituitary adenylate cyclase-activating polypeptide (PACAP)-27, PACAP-38, and maxadilan [PACAP type 1 (PAC1) agonist] each stimulated ANP secretion. The PAC1 antagonist M65 1) abolished PACAP-27/38-stimulated ANP secretion; 2) inhibited basal ANP secretion by 28 +/- 5%, implying that endogenous PACAP stimulates ANP secretion; and 3) converted the ANP response to DMPP from 109 +/- 21% above to 40 +/- 5% below basal, unmasking the cholinergic component and indicating that DMPP activated PACAP neurons that stimulate ANP secretion. Combined atropine and M65 restored DMPP-stimulated ANP secretion to basal levels. ANP secretion in the antrum is thus regulated by intramural cholinergic and PACAP neurons; cholinergic neurons inhibit and PACAP neurons stimulate ANP secretion.

Animals↗

PubMed2002

Four cardiac hormones increase circulating concentrations of luteinizing hormone and testosterone.

This study was designed to determine whether four peptide hormones consisting of amino acids 1-30-long-acting natriuretic hormone (LANH), 31-67 (vessel dilator), 79-98 (kaliuretic hormone), and 99-126 (atrial natriuretic hormone [ANH])-of the 126 amino acid atrial natriuretic prohormone increase the circulating concentration of testosterone in healthy humans (n = 30). Vessel dilator, kaliuretic hormone, LANH, and ANH increased the circulating concentration of testosterone 3.8, 2.6, 3.9, and 3.4-fold, respectively (p < 0.01 for each), when infused at 100 ng/(kg of body wt . min) for 60 min. The increases in testosterone lasted 2.5-3 h after cessation of the respective atrial natriuretic peptides' infusions. ANH, vessel dilator, LANH, and kaliuretic hormone increased luteinizing hormone (LH) 3-to 8.4-fold (p < 0.001) during infusion, with the maximal increase in LH being 6.7- to 11.7-fold (p < 0.001) secondary to these cardiac hormones. Vessel dilator and kaliuretic hormone increased LH before increasing testosterone in a sequential fashion. These data suggest that four peptide hormones-ANH, LANH, vessel dilator, and kaliuretic hormone-increase the circulating con-centrations of LH and testosterone in humans.

Adult↗