The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Carlos M Ferrario - One of the best experts on this subject based on the ideXlab platform.
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abstract p2033 rationale for a novel approach to hypertension treatment based on immuno neutralization of Angiotensin 1 12 catalytic sites with a polyclonal antibody
Hypertension, 2019Co-Authors: Sarfaraz Ahmad, Kendra N Wright, Jasmina Varagic, Leanne Groban, Carlos M FerrarioAbstract:The biochemical pathways for the formation of biological active Angiotensins continues to undergo significant revision with the demonstration of Angiotensin-(1-12) as an endogenous substrate formin...
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New Physiological Concepts of the Renin-Angiotensin System From the Investigation of Precursors and Products
2016Co-Authors: Of Angiotensin I Metabolism, Carlos M FerrarioAbstract:Research on the regulatory actions of the renin-angioten-sin system (RAS) continues to provide a wealth of information on how cells maintain their internal homeostatic environment, regulate metabolic processes, and adapt or contribute to disease. Not that long ago, the active product of the system, Angiotensin II (Ang II), was considered the single critical hormone product of an endocrine system involved in regulating blood volume and vascular tone. A revised concept emerged after the demonstration that renin and angioten-sinogen (Aogen) are present in tissues. These findings sug-gested that the RAS is composed of dual, independently regulated, blood-borne and tissue systems. Today, a broader and more complex system is being revealed by advanced genetic and molecular tools, as well as by the outcome of clinical studies using medications selective for 1 of the proteins contributing to the generation of Angiotensin peptides. Recognition that the RAS contains both a pressor and depressor arm in exerting regulatory functions on vascular tone and cellular signaling paved the way for the generation of an alternate hypothesis as to how an imbalance of their function contributes to cardiovascular disease.1 This review summarizes the data supporting the hypothesis of a counter-regulatory arm that, within the RAS, opposes the actions of Ang II. We build on these earlier discoveries to provide a new insight into an additional pathway in which an extended form of Angiotensin I (Ang I), proAngiotensin-12 (Ang-[1-12]), may be an alternate substrate for the production of the biological active Angiotensins. A comprehensive evaluation of this topic cannot be achieved within the assigned space; therefore, only the key elements of the topic will be ad-dressed, asking for indulgence in not providing a detailed listing of all of the published studies
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Angiotensin 1 12 a chymase mediated cellular Angiotensin ii substrate
Current Hypertension Reports, 2014Co-Authors: Sarfaraz Ahmad, Jasmina Varagic, Leanne Groban, Louis J Dellitalia, Sayaka Nagata, Neal D Kon, Carlos M FerrarioAbstract:The classical view of biochemical pathways for the formation of biologically active Angiotensins continues to undergo significant revision as new data uncovers the existence of important species differences between humans and rodents. The discovery of two novel substrates that, cleaved from Angiotensinogen, can lead to direct tissue Angiotensin II formation has the potential of radically altering our understanding of how tissues source Angiotensin II production and explain the relative lack of efficacy that characterizes the use of Angiotensin converting enzyme inhibitors in cardiovascular disease. This review addresses the discovery of Angiotensin-(1-12) as an endogenous substrate for the production of biologically active Angiotensin peptides by a non-renin dependent mechanism and the revealing role of cardiac chymase as the Angiotensin II convertase in the human heart. This new information provides a renewed argument for exploring the role of chymase inhibitors in the correction of cardiac arrhythmias and left ventricular systolic and diastolic dysfunction.
Vardan T Karamyan - One of the best experts on this subject based on the ideXlab platform.
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identification of membrane bound variant of metalloendopeptidase neurolysin ec 3 4 24 16 as the non Angiotensin type 1 non at1 non at2 Angiotensin binding site
Journal of Biological Chemistry, 2012Co-Authors: Naomi J Wangler, Kira L Santos, Ines Schadock, Fred K Hagen, Michael Bader, Robert C Speth, Emanuel Escher, Vardan T KaramyanAbstract:Abstract Recently, we discovered a novel non-Angiotensin type 1 (non-AT1), non-AT2 Angiotensin binding site in rodent and human brain membranes, which is distinctly different from Angiotensin receptors and key proteases processing Angiotensins. It is hypothesized to be a new member of the renin-Angiotensin system. This study was designed to isolate and identify this novel Angiotensin binding site. An Angiotensin analog, photoaffinity probe 125I-SBpa-Ang II, was used to specifically label the non-AT1, non-AT2 Angiotensin binding site in mouse forebrain membranes, followed by a two-step purification procedure based on the molecular size and isoelectric point of the photoradiolabeled binding protein. Purified samples were subjected to two-dimensional gel electrophoresis followed by mass spectrometry identification of proteins in the two-dimensional gel sections containing radioactivity. LC-MS/MS analysis revealed eight protein candidates, of which the four most abundant were immunoprecipitated after photoradiolabeling. Immunoprecipitation studies indicated that the Angiotensin binding site might be the membrane-bound variant of metalloendopeptidase neurolysin (EC 3.4.24.16). To verify these observations, radioligand binding and photoradiolabeling experiments were conducted in membrane preparations of HEK293 cells overexpressing mouse neurolysin or thimet oligopeptidase (EC 3.4.24.15), a closely related metalloendopeptidase of the same family. These experiments also identified neurolysin as the non-AT1, non-AT2 Angiotensin binding site. Finally, brain membranes of mice lacking neurolysin were nearly devoid of the non-AT1, non-AT2 Angiotensin binding site, further establishing membrane-bound neurolysin as the binding site. Future studies will focus on the functional significance of this highly specific, high affinity interaction between neurolysin and Angiotensins.
Michael Bader - One of the best experts on this subject based on the ideXlab platform.
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identification of membrane bound variant of metalloendopeptidase neurolysin ec 3 4 24 16 as the non Angiotensin type 1 non at1 non at2 Angiotensin binding site
Journal of Biological Chemistry, 2012Co-Authors: Naomi J Wangler, Kira L Santos, Ines Schadock, Fred K Hagen, Michael Bader, Robert C Speth, Emanuel Escher, Vardan T KaramyanAbstract:Abstract Recently, we discovered a novel non-Angiotensin type 1 (non-AT1), non-AT2 Angiotensin binding site in rodent and human brain membranes, which is distinctly different from Angiotensin receptors and key proteases processing Angiotensins. It is hypothesized to be a new member of the renin-Angiotensin system. This study was designed to isolate and identify this novel Angiotensin binding site. An Angiotensin analog, photoaffinity probe 125I-SBpa-Ang II, was used to specifically label the non-AT1, non-AT2 Angiotensin binding site in mouse forebrain membranes, followed by a two-step purification procedure based on the molecular size and isoelectric point of the photoradiolabeled binding protein. Purified samples were subjected to two-dimensional gel electrophoresis followed by mass spectrometry identification of proteins in the two-dimensional gel sections containing radioactivity. LC-MS/MS analysis revealed eight protein candidates, of which the four most abundant were immunoprecipitated after photoradiolabeling. Immunoprecipitation studies indicated that the Angiotensin binding site might be the membrane-bound variant of metalloendopeptidase neurolysin (EC 3.4.24.16). To verify these observations, radioligand binding and photoradiolabeling experiments were conducted in membrane preparations of HEK293 cells overexpressing mouse neurolysin or thimet oligopeptidase (EC 3.4.24.15), a closely related metalloendopeptidase of the same family. These experiments also identified neurolysin as the non-AT1, non-AT2 Angiotensin binding site. Finally, brain membranes of mice lacking neurolysin were nearly devoid of the non-AT1, non-AT2 Angiotensin binding site, further establishing membrane-bound neurolysin as the binding site. Future studies will focus on the functional significance of this highly specific, high affinity interaction between neurolysin and Angiotensins.
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tissue renin Angiotensin aldosterone systems targets for pharmacological therapy
Annual Review of Pharmacology and Toxicology, 2010Co-Authors: Michael BaderAbstract:The renin-Angiotensin-aldosterone system is one of the most important systems in cardiovascular control and in the pathogenesis of cardiovascular diseases. Therefore, it is already a very successful drug target for the therapy of these diseases. However, Angiotensins are generated not only in the plasma but also locally in tissues from precursors and substrates either locally expressed or imported from the circulation. In most areas of the brain, only locally generated Angiotensins can exert effects on their receptors owing to the blood-brain barrier. Other tissue renin-Angiotensin-aldosterone systems are found in cardiovascular organs such as kidney, heart, and vessels and play important roles in the function of these organs and in the deleterious actions of hypertension and diabetes on these tissues. Novel components with mostly opposite actions to the classical renin-Angiotensin-aldosterone systems have been described and need functional characterization to evaluate their suitability as novel drug targets.
Naomi J Wangler - One of the best experts on this subject based on the ideXlab platform.
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identification of membrane bound variant of metalloendopeptidase neurolysin ec 3 4 24 16 as the non Angiotensin type 1 non at1 non at2 Angiotensin binding site
Journal of Biological Chemistry, 2012Co-Authors: Naomi J Wangler, Kira L Santos, Ines Schadock, Fred K Hagen, Michael Bader, Robert C Speth, Emanuel Escher, Vardan T KaramyanAbstract:Abstract Recently, we discovered a novel non-Angiotensin type 1 (non-AT1), non-AT2 Angiotensin binding site in rodent and human brain membranes, which is distinctly different from Angiotensin receptors and key proteases processing Angiotensins. It is hypothesized to be a new member of the renin-Angiotensin system. This study was designed to isolate and identify this novel Angiotensin binding site. An Angiotensin analog, photoaffinity probe 125I-SBpa-Ang II, was used to specifically label the non-AT1, non-AT2 Angiotensin binding site in mouse forebrain membranes, followed by a two-step purification procedure based on the molecular size and isoelectric point of the photoradiolabeled binding protein. Purified samples were subjected to two-dimensional gel electrophoresis followed by mass spectrometry identification of proteins in the two-dimensional gel sections containing radioactivity. LC-MS/MS analysis revealed eight protein candidates, of which the four most abundant were immunoprecipitated after photoradiolabeling. Immunoprecipitation studies indicated that the Angiotensin binding site might be the membrane-bound variant of metalloendopeptidase neurolysin (EC 3.4.24.16). To verify these observations, radioligand binding and photoradiolabeling experiments were conducted in membrane preparations of HEK293 cells overexpressing mouse neurolysin or thimet oligopeptidase (EC 3.4.24.15), a closely related metalloendopeptidase of the same family. These experiments also identified neurolysin as the non-AT1, non-AT2 Angiotensin binding site. Finally, brain membranes of mice lacking neurolysin were nearly devoid of the non-AT1, non-AT2 Angiotensin binding site, further establishing membrane-bound neurolysin as the binding site. Future studies will focus on the functional significance of this highly specific, high affinity interaction between neurolysin and Angiotensins.
Tadashi Inagami - One of the best experts on this subject based on the ideXlab platform.
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Original Contributions Significance of Vascular Renin for Local Generation of Angiotensins
2016Co-Authors: Koichi Higashimori, Joachim Gante, Gunter Holzemann, Tadashi InagamiAbstract:The effects of specific renin inhibitors, Angiotensin converting enzyme inhibitors, indometh-acin, and prostaglandin I2 analogue on the release of Angiotensins from isolated and Krebs-Ringer-perfused rabbit mesenteric arteries were examined. Three different renin inhibitors suppressed release of Angiotensins in dose-dependent manners. At the highest concentration (10~7 M), the inhibitors EMD 52,620, EMD 54,388, and EMD 52,742 induced 46%, 52%, and 48 % decreases, respectively, in the basal rate of immunoreactive Angiotensin II release. These results provide clear evidence that released Angiotensins are produced by the specific action of vascular renin and that the renin inhibitors suppress the vascular renin-Angiotensin system as well as the circulating renin-Angiotensin system and appear to provide a useful mode for the treatment of hypertension. Nonsulfhydryl Angiotensin converting enzyme inhibitors cilazapril and delapril were more effective than captopril, and ramipril was equipotent to captopril, suggesting that the effectiveness of Angiotensin converting enzyme inhibitors on the vascular renin-Angiotensin system cannot be explained only by its inhibitory effect on Angiotensin converting enzyme. Indomethacin, which was reported to suppress Angiotensin II release from rat hind limbs, elicited a dose-dependent increase of angiotensi
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steroid hormones upregulate rat Angiotensin ii type 1a receptor gene role of glucocorticoid responsive elements in rat Angiotensin ii type 1a promoter
The Journal of Steroid Biochemistry and Molecular Biology, 1995Co-Authors: Tadashi InagamiAbstract:Abstract The transcription of the rat Angiotensin II type 1A receptor gene is stimulated by glucocorticoids. To clarify the molecular mechanism for glucocorticoid action in rat vascular smooth muscle cells, we investigated the effects of dexamethasone on the promoter activity of the Angiotensin II type 1A receptor by using promoter/luciferase reporter gene constructs and heterologous context constructs (containing the thymidine kinase promoter) in transfected vascular smooth muscle cells. There are three putative glucocorticoid responsive elements in the promoter. However, only one glucocorticoid responsive element was found to respond to dexamethasone (1 μM). The region was located at positions, −756 to −770 bp upstream of the transcription initiation site. A glucocorticoid antagonist, RU38486, completely blocked the induction by dexamethasone, suggesting that the glucocorticoid responsive element was functional through a specific glucocorticoid receptor. Compared with the angiotension II type 1A receptor promoter, no effect by dexamethasone was observed in vascular smooth muscle cells transfected with the Angiotensin II type 1B receptor promoter/luciferase reporter gene constructs. We concluded that the dexamethasone-induced increase in the transcription of the Angiotensin II type 1A receptor gene occurred through the binding to GRE up the glucocorticoid-specific receptor.
