Attenuation of atrial natriuretic peptide response to sodium loading after cardiac operation

To evaluate the role of cardiac operation and the atrial appendage in secretion of atrial natriuretic peptide in response to sodium loading, we studied 44 patients who underwent heart operations with (28 patients; group I) or without (16 patients; group II) right atrial appendectomy and 16 patients who underwent lobectomy (group III). Before and after operation 1 ml/kg of 10% NaCl was infused for 15 minutes. Blood samples were taken before NaCl infusion and immediately after infusion and at 60 minutes after infusion. There were no significant changes in hemodynamics or hematocrit level throughout the study. Plasma and urine sodium levels and the fractional excretion of sodium were significantly increased by sodium loading. Before operation, plasma mean atrial natriuretic peptide levels increased markedly in response to sodium infusion in all groups. After operation, this atrial natriuretic peptide response disappeared in groups I and II, but remained present in group III. Elution profiles of plasma atrial natriuretic peptide showed that the major peak coincided with α-atrial natriuretic peptide before sodium loading, whereas a β-atrial natriuretic peptide peak appeared 60 minutes after sodium loading in all groups both before and after operation. The mean plasma arginine vasopressin levels were significantly increased by sodium loading both before and after operation in all groups. Sodium loading decreased the mean plasma aldosterone levels in all groups before operation, but did not after operation in groups I and II. Plasma renin activity and angiotensin II concentrations were not changed by sodium loading. We conclude that atrial natriuretic peptide response to sodium loading is attenuated by cardiac operation irrespective of right appendectomy, but not by lobectomy. Sodium loading augments secretion of β-atrial natriuretic peptide even in reduced atrial natriuretic peptide response states after heart operations

Th2-predominant inflammation and blockade of IFN-γ signaling induce aneurysms in allografted aortas

Abdominal aortic aneurysms (AAAs) cause death due to complications related to expansion and rupture. The underlying mechanisms that drive AAA development remain largely unknown. We recently described evidence for a shift toward T helper type 2 (Th2) cell responses in human AAAs compared with stenotic atheromas. To evaluate putative pathways in AAA formation, we induced Th1- or Th2-predominant cytokine environments in an inflammatory aortic lesion using murine aortic transplantation into WT hosts or those lacking the receptors for the hallmark Th1 cytokine IFN-γ, respectively. Allografts in WT recipients developed intimal hyperplasia, whereas allografts in IFN-γ receptor–deficient (GRKO) hosts developed severe AAA formation associated with markedly increased levels of MMP-9 and MMP-12. Allografts in GRKO recipients treated with anti–IL-4 antibody to block the characteristic IL-4 Th2 cytokine or allografts in GRKO hosts also congenitally deficient in IL-4 did not develop AAA and likewise exhibited attenuated collagenolytic and elastolytic activities. These observations demonstrate an important dichotomy between cellular immune responses that induce IFN-γ– or IL-4–dominated cytokine environments. The findings establish important regulatory roles for a Th1/Th2 cytokine balance in modulating matrix remodeling and have important implications for the pathophysiology of AAAs and arteriosclerosis

Endothelin-receptor antagonists are proapoptotic and antiproliferative in human colon cancer cells

Endothelin (ET)-1 can act as an autocrine/paracrine growth factor or an antiapoptotic factor in human cancers. To study the role of ET-1 in human colon cancer, proliferation and apoptosis of colon carcinoma cells was investigated using human HT-29 and SW480 colon carcinoma cells. ET-1 was secreted by these cells. Treatment of cells with bosentan, a dual ET(A/B)-receptor antagonist, decreased cell number. Inhibition of DNA synthesis by bosentan was observed only in the presence of serum. Exogenously added ET-1 did not increase DNA synthesis in serum-deprived cells. SW480 cells were sensitive and HT-29 cells were resistant to FasL-induced apoptosis. Bosentan sensitised resistant HT-29 cells to FasL-induced, caspase-mediated apoptosis, but not to TNF-alpha-induced apoptosis. Bosentan and/or FasLigand (FasL) did not modulate the expression of caspase-8 or FLIP. Bosentan sensitisation to apoptosis was reversed by low concentrations (10(-13)-10(-10) M), but not by high concentrations (10(-9)-10(-7) M) of ET-1. These results suggest that the binding of ET-1 to high-affinity sites inhibits FasL-induced apoptosis, while the binding of either ET-1 or receptor antagonists to low-affinity sites promotes FasL-induced apoptosis. In conclusion, endothelin signalling pathways do not induce human colon cancer cell proliferation, but are survival signals controling resistance to apoptosis

Genome-Wide Expression of Azoospermia Testes Demonstrates a Specific Profile and Implicates ART3 in Genetic Susceptibility

Infertility affects about one in six couples attempting pregnancy, with the man responsible in approximately half of the cases. Because the pathophysiology underlying azoospermia is not elucidated, most male infertility is diagnosed as idiopathic. Genome-wide gene expression analyses with microarray on testis specimens from 47 non-obstructive azoospermia (NOA) and 11 obstructive azoospermia (OA) patients were performed, and 2,611 transcripts that preferentially included genes relevant to gametogenesis and reproduction according to Gene Ontology classification were found to be differentially expressed. Using a set of 945 of the 2,611 transcripts without missing data, NOA was further categorized into three classes using the non-negative matrix factorization method. Two of the three subclasses were different from the OA group in Johnsen's score, FSH level, and/or LH level, while there were no significant differences between the other subclass and the OA group. In addition, the 52 genes showing high statistical difference between NOA subclasses (p < 0.01 with Tukey's post hoc test) were subjected to allelic association analyses to identify genetic susceptibilities. After two rounds of screening, SNPs of the ADP-ribosyltransferase 3 gene (ART3) were associated with NOA with highest significance with ART3-SNP25 (rs6836703; p = 0.0025) in 442 NOA patients and 475 fertile men. Haplotypes with five SNPs were constructed, and the most common haplotype was found to be under-represented in patients (NOA 26.6% versus control 35.3%, p = 0.000073). Individuals having the most common haplotype showed an elevated level of testosterone, suggesting a protective effect of the haplotype on spermatogenesis. Thus, genome-wide gene expression analyses were used to identify genes involved in the pathogenesis of NOA, and ART3 was subsequently identified as a susceptibility gene for NOA. These findings clarify the molecular pathophysiology of NOA and suggest a novel therapeutic target in the treatment of NOA

Serotonin enhances the production of type IV collagen by human mesangial cells

Serotonin enhances the production of type IV collagen by human mesangial cells.BackgroundThe plasma concentration of 5-hydroxytryptamine (5-HT) in diabetic patients is higher than that in normal subjects. Since recent reports have demonstrated the presence of 5-HT2A receptor in glomerular mesangial cells, it is possible that 5-HT may be involved in the development of diabetic nephropathy through the 5-HT2A receptor in mesangial cells. Because expansion of the glomerular mesangial lesion is a characteristic feature of diabetic nephropathy, we examined the effect of 5-HT on the production of type IV collagen by human mesangial cells.MethodsHuman mesangial cells were incubated with 5-HT with or without 5-HT receptor antagonists, protein kinase C (PKC) inhibitor or transforming growth factor-β (TGF-β) antibody. Type IV collagen mRNA and protein concentration in medium were measured by Northern blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. TGF-β mRNA and bioactivity in the medium were measured by Northern blot analysis and bioassay using mink lung epithelial cells, respectively.Results5-HT stimulated the production of type IV collagen by human mesangial cells, which was inhibited by ketanserin and sarpogrelate hydrochloride, 5-HT2A receptor antagonists, but not by ondansetron, a 5-HT3 receptor antagonist. 5-HT increased the bioactivities of both active and total TGF-β. However, the 5-HT-enhanced production of type IV collagen was completely inhibited by an anti-TGF-β antibody. Furthermore, a PKC inhibitor, calphostin C, inhibited the 5-HT-induced increase in type IV collagen secretion, and the activity of membrane PKC was increased by 5-HT. Phorbol ester activated type IV collagen production as well as active and total TGF-β. Calphostin C completely inhibited the 5-HT-enhanced activity of active TGF-β, but did not inhibit exogenous TGF-β-induced increase in type IV collagen secretion.ConclusionsOur results suggest that 5-HT-enhanced production of type IV collagen by human mesangial cells is mediated by activation of PKC and subsequent increase in active TGF-β activity

Salusins: Potential Use as a Biomarker for Atherosclerotic Cardiovascular Diseases

Human salusin-α and salusin-β are related peptides produced from prosalusin. Bolus injection of salusin-β into rats induces more profound hypotension and bradycardia than salusin-α. Central administration of salusin-β increases blood pressure via release of norepinephrine and arginine-vasopressin. Circulating levels of salusin-α and salusin-β are lower in patients with essential hypertension. Salusin-β exerts more potent mitogenic effects on human vascular smooth muscle cells (VSMCs) and fibroblasts than salusin-α. Salusin-β accelerates inflammatory responses in human endothelial cells and monocyte-endothelial adhesion. Human macrophage foam cell formation is stimulated by salusin-β but suppressed by salusin-α. Chronic salusin-β infusion into apolipoprotein E-deficient mice enhances atherosclerotic lesions; salusin-α infusion reduces lesions. Salusin-β is expressed in proliferative neointimal lesions of porcine coronary arteries after stenting. Salusin-α and salusin-β immunoreactivity have been detected in human coronary atherosclerotic plaques, with dominance of salusin-β in macrophage foam cells, VSMCs, and fibroblasts. Circulating salusin-β levels increase and salusin-α levels decrease in patients with coronary artery disease. These findings suggest that salusin-β and salusin-α may contribute to proatherogenesis and antiatherogenesis, respectively. Increased salusin-β and/or decreased salusin-α levels in circulating blood and vascular tissue are closely linked with atherosclerosis. Salusin-α and salusin-β could be candidate biomarkers and therapeutic targets for atherosclerotic cardiovascular diseases

Retrospective Analysis on the Efficacy, Safety and Treatment Failure Group of Sitagliptin for Mean 10-Month Duration

BackgroundTo investigate the clinical results of sitagliptin (SITA) and the characteristics of the treatment failure group or of low responders to SITA.MethodsA retrospective study of type 2 diabetic patients reviewed 99 cases, including 12 treatment failure cases, who stopped SITA because of worsening patients' condition, and 87 cases, who continued treatment over five visits (total 9.9±10.1 months) after receiving the prescription of SITA from December 2008 to June 2009. Subjects were classified as five groups administered SITA as an initial combination with metformin (MET), add-on to metformin or sulfonylurea, and switching from sulfonylurea or thiazolidinedione. The changes in HbA1c level from the first to last visit (ΔHbA1c) in treatment maintenance group were subanalyzed.ResultsThe HbA1c level was significantly reduced in four groups, including initial coadministration of SITA with metformin (ΔHbA1c=-1.1%, P<0.001), add-on to MET (ΔHbA1c=-0.6%, P=0.017), add-on to sulfonylurea (ΔHbA1c=-0.5%, P<0.001), and switching from thiazolidinedione (ΔHbA1c=-0.3%, P=0.013). SITA was noninferior to sulfonlyurea (ΔHbA1c=-0.2%, P=0.63). There was no significant adverse effect. The treatment failure group had a longer diabeties duration (P=0.008), higher HbA1c (P=0.001) and fasting plasma glucose (P=0.003) compared to the maintenance group. Subanalysis on the tertiles of ΔHbA1c showed that low-response to SITA (tertile 1) was associated with a longer diabetes duration (P=0.009) and lower HbA1c (P<0.001).ConclusionSITA was effective and safe for use in Korean type 2 diabetic patients. However, its clinical responses and long-term benefit-harm profile is yet to be established