Disruption of Drosophila melanogaster Lipid Metabolism Genes Causes Tissue Overgrowth Associated with Altered Developmental Signaling.

Developmental patterning requires the precise interplay of numerous intercellular signaling pathways to ensure that cells are properly specified during tissue formation and organogenesis. The spatiotemporal function of many developmental pathways is strongly influenced by the biosynthesis and intracellular trafficking of signaling components. Receptors and ligands must be trafficked to the cell surface where they interact, and their subsequent endocytic internalization and endosomal trafficking is critical for both signal propagation and its down-modulation. In a forward genetic screen for mutations that alter intracellular Notch receptor trafficking in Drosophila melanogaster, we recovered mutants that disrupt genes encoding serine palmitoyltransferase and acetyl-CoA carboxylase. Both mutants cause Notch, Wingless, the Epidermal Growth Factor Receptor (EFGR), and Patched to accumulate abnormally in endosomal compartments. In mosaic animals, mutant tissues exhibit an unusual non-cell-autonomous effect whereby mutant cells are functionally rescued by secreted activities emanating from adjacent wildtype tissue. Strikingly, both mutants display prominent tissue overgrowth phenotypes that are partially attributable to altered Notch and Wnt signaling. Our analysis of the mutants demonstrates genetic links between abnormal lipid metabolism, perturbations in developmental signaling, and aberrant cell proliferation

Reply to Visit‐to‐Visit Blood Pressure Variation: Time to Reanalyze All The Data From the TROPHY Study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97448/1/jch12069.pd

Desensitization of angiotensin receptor function

Desensitization of angiotensin receptor function. Angiotensin II is an eight amino acid peptide which plays a major role in the regulation of cardiovascular homeostasis. The physiologic effects of angiotensin (Ang) II are mediated by a G-protein coupled receptor, termed AT1, which activates phospholipase C. A major factor regulating angiotensin II receptor function is the rapid desensitization following agonist stimulation. However, despite years of investigation, the mechanism by which the angiotensin receptor is regulated remains unclear. The cloning of the AT-1 receptor and the availability of cell lines which stabily express this receptor has helped elucidate these mechanisms. In this paper, we review the data from our laboratory concerning the post-translational regulation of the angiotensin receptor function

Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2

Understanding mechanisms that contribute to the regression of glomerulosclerosis is important for developing new strategies to treat chronic kidney disease. We reported that transient high-dose treatment with an angiotensin receptor blocker causes regression of renal arteriolar hypertrophy and hypertension in spontaneously hypertensive rats. To extend those findings to another form of kidney disease, we examined the short- and long-term effects of transient high-dose angiotensin receptor blocker treatment in a mouse model of adriamycin-induced glomerulosclerosis. A 2-week course of candesartan caused a dose-dependent regression of established glomerulosclerotic lesions sustained for over 6 months following cessation of treatment. Highly sensitive in situ zymography and activity assays showed that glomerular matrix metalloproteinase (MMP)-2 activity was increased after high-dose angiotensin blocker therapy. Treatment of cultured podocytes with candesartan resulted in an increase in MMP-2 activity. The regression of glomerulosclerosis was partially attenuated in mice pretreated with the MMP inhibitor doxycycline, as well as in MMP-2 knockout mice. Our results suggest that transient high-dose angiotensin receptor blocker treatment effectively induced sustained regression of glomerulosclerosis by a mechanism mediated, in part, by changes in MMP-2 activity

Iodate respiration by Azoarcus sp. DN11 and its potential use for removal of radioiodine from contaminated aquifers

Azoarcus sp. DN11 was previously isolated from gasoline-contaminated groundwater as an anaerobic benzene-degrading bacterium. Genome analysis of strain DN11 revealed that it contained a putative idr gene cluster (idrABP1P2), which was recently found to be involved in bacterial iodate (IO3−) respiration. In this study, we determined if strain DN11 performed iodate respiration and assessed its potential use to remove and sequester radioactive iodine (129I) from subsurface contaminated aquifers. Strain DN11 coupled acetate oxidation to iodate reduction and grew anaerobically with iodate as the sole electron acceptor. The respiratory iodate reductase (Idr) activity of strain DN11 was visualized on non-denaturing gel electrophoresis, and liquid chromatography–tandem mass spectrometry analysis of the active band suggested the involvement of IdrA, IdrP1, and IdrP2 in iodate respiration. The transcriptomic analysis also showed that idrA, idrP1, and idrP2 expression was upregulated under iodate-respiring conditions. After the growth of strain DN11 on iodate, silver-impregnated zeolite was added to the spent medium to remove iodide from the aqueous phase. In the presence of 200 μM iodate as the electron acceptor, more than 98% of iodine was successfully removed from the aqueous phase. These results suggest that strain DN11 is potentially helpful for bioaugmentation of 129I-contaminated subsurface aquifers

Withdrawal of antihypertensive medication: a systematic review

Although antihypertensive medication is usually continued indefinitely, observations during wash-out phases in hypertension trials have shown that withdrawal of antihypertensive medication might be well tolerated to do in a considerable proportion of people. A systematic review was completed to determine the proportion of people remaining normotensive for 6 months or longer after cessation of antihypertensive therapy and to investigate the safety of withdrawal. The mean proportion adjusted for sample size of people remaining below each study's threshold for hypertension treatment was 0.38 at 6 months [95% confidence interval (CI) 0.37–0.49; 912 participants], 0.40 at 1 year (95% CI 0.40–0.40; 2640 participants) and 0.26 at 2 years or longer (95% CI 0.26–0.27; 1262 participants). Monotherapy, lower blood pressure before withdrawal and body weight were reported as predictors for successful withdrawal. Adverse events were more common in those who withdrew but were minor and included headache, joint pain, palpitations, oedema and a general feeling of being unwell. Prescribers should consider offering patients with well controlled hypertension a trial of withdrawal of antihypertensive treatment with subsequent regular blood pressure monitoring

Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

<p>Abstract</p> <p>Background</p> <p>Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease.</p> <p>Methods</p> <p>Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ET_A) and type B (ET_B), and angiotensin type 1 (AT₁) and type 2 (AT₂) receptors expression and function were examined using immunohistochemistry, Western blot and <it>in vitro </it>pharmacology.</p> <p>Results</p> <p>ET_Aand, to a lesser extent, ET_Breceptor staining was observed in the healthy vascular smooth muscle cells. The level of ET_Breceptor expression was higher in patients undergoing CABG surgery (250% ± 23%; P < 0.05) and in the patients with angina pectoris (199% ± 6%; P < 0.05), than in the healthy controls (100% ± 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ET_Breceptor agonist sarafotoxin S6c, compared to healthy controls (P < 0.05). No such difference was found for the ET_Areceptors. AT₁and, to a lesser extent, AT₂receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT₁receptor expression was higher in both the angina pectoris (128% ± 25%; P < 0.05) and in the CABG patients (203% ± 41%; P < 0.05), as compared to the healthy controls (100% ± 25%). The increased AT₁receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s).</p> <p>Conclusion</p> <p>The results demonstrate, for the first time, upregulation of ET_Band AT₁receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.</p