Michael Bader

Publications of Michael Bader

• Therapeutic targeting of the angiotensin-converting enzyme 2/Angiotensin-(1-7)/Mas cascade in the renin-angiotensin system: a patent review.

  Authors: Anderson J Ferreira, Michael Bader, Robson As Santos

  Expert opinion on therapeutic patents. 04/2012;

  Introduction: The renin-angiotensin system (RAS) is a main therapeutic target for cardiovascular diseases. Within the last two decades, novel components of the RAS have been discovered, opening newIntroduction: The renin-angiotensin system (RAS) is a main therapeutic target for cardiovascular diseases. Within the last two decades, novel components of the RAS have been discovered, opening new opportunities to interfere with its activity. Angiotensin(Ang)-(1-7) is synthesized by angiotensin-converting enzyme 2 (ACE2), and interacts with the G-protein-coupled receptor Mas. The axis formed by ACE2/Ang-(1-7)/Mas represents an endogenous counter regulatory pathway within the RAS. Areas covered: In this review, the authors discuss patents and recent initiatives to develop therapeutic strategies based on the ACE2/Ang-(1-7)/Mas axis. Expert opinion: Many publications and patents support a strategy to interfere with the activity of the RAS by stimulating its counter-regulatory axis mainly in two different ways: i) To increase the activity of ACE2, which will impact the system by increasing the inactivation of Ang II and the production of Ang-(1-7); ii) To stimulate Mas, taking advantage of nanostructured formulations of the natural peptide or analogues of Ang-(1-7). Although the preclinical studies are compelling, the possible impact of these novel therapeutic tools for the treatment of cardiometabolic diseases will only be known after completion of the ongoing clinical studies.

• Emergence and evolution of the renin-angiotensin-aldosterone system.

  Authors: David Fournier, Friedrich C Luft, Michael Bader, Detlev Ganten, Miguel A Andrade-Navarro

  Journal of molecular medicine (Berlin, Germany). 04/2012;

  The renin-angiotensin-aldosterone system (RAAS) is not the sole, but perhaps the most important volume regulator in vertebrates. To gain insights into the function and evolution of its components, weThe renin-angiotensin-aldosterone system (RAAS) is not the sole, but perhaps the most important volume regulator in vertebrates. To gain insights into the function and evolution of its components, we conducted a phylogenetic analysis of its main related genes. We found that important parts of the system began to appear with primitive chordates and tunicates and that all major components were present at the divergence of bony fish, with the exception of the Mas receptor. The Mas receptor first appears after the bony-fish/tetrapod divergence. This phase of evolutionary innovation happened about 400 million years ago. We found solid evidence that angiotensinogen made its appearance in cartilage fish. The presence of several RAAS genes in organisms that lack all the components shows that these genes have had other ancestral functions outside of their current role. Our analysis underscores the utility of sequence comparisons in the study of evolution. Such analyses may provide new hypotheses as to how and why in today's population an increased activity of the RAAS frequently leads to faulty salt and volume regulation, hypertension, and cardiovascular diseases, opening up new and clinically important research areas for evolutionary medicine.

• Cardiovascular responses evoked by activation or blockade of GABA(A) receptors in the hypothalamic PVN are attenuated in transgenic rats with low brain angiotensinogen.

  Authors: Ana Quênia Gomes da Silva, Carlos Henrique Xavier, Maria Jose Campagnole-Santos, Sordaini M Caligiorne, Ovidiu C Baltatu, Michael Bader, Robson Augusto S Santos, Marco Antônio P Fontes

  Brain research. 02/2012; 1448:101-10.

  Previous evidence indicates that a balance between inhibitory gabaergic and excitatory angiotensinergic factors in the PVN is important for cardiovascular control. We investigated the cardiovascularPrevious evidence indicates that a balance between inhibitory gabaergic and excitatory angiotensinergic factors in the PVN is important for cardiovascular control. We investigated the cardiovascular response evoked from activation or blockade of GABA(A) receptors in the paraventricular nucleus (PVN), in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)]. Brain Ang II and Ang-(1-7) levels were also determined. In functional experiments, TGR(ASrAOGEN) and Sprague-Dawley rats (SD, control) were anesthetized with urethane and blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. Brain Ang II and Ang-(1-7) levels were largely reduced in TGR(ASrAOGEN) compared with SD rats. Inhibition of PVN neurons with the GABA(A) agonist, muscimol (1nmol/100nL), resulted in an attenuated fall in all cardiovascular variables in TGR(ASrAOGEN) compared with SD rats. This difference was particularly pronounced in HR (TGR Mus -23±6bpm vs. -77±9bpm SD Mus; P<0.05) and RSNA (TGR -3±10% vs.-29±8% SD; P<0.05). Furthermore, the sympathetic response evoked by blockade of GABA(A) receptors in the PVN of TGR(ASrAOGEN) was also largely suppressed. The present data indicate that the sympathetic outflow mediated by PVN neurons under basal conditions is suppressed in TGR(ASrAOGEN) rats corroborating the functional significance of brain angiotensin production in the central regulation of sympathetic output to the cardiovascular system.

• Angiotensin-(1-7) receptor Mas is an essential modulator of extracellular matrix protein expression in the heart.

  Authors: Elisandra Gava, Carlos Henrique de Castro, Anderson J Ferreira, Heloísa Colleta, Marcos B Melo, Natalia Alenina, Michael Bader, Laser A Oliveira, Robson A S Santos, Gregory T Kitten

  Regulatory peptides. 01/2012;

  In this study we investigated the effects of genetic deletion of the Angiotensin-(1-7) receptor Mas or the Angiotensin II receptor AT(2) on the expression of specific extracellular matrix (ECM)In this study we investigated the effects of genetic deletion of the Angiotensin-(1-7) receptor Mas or the Angiotensin II receptor AT(2) on the expression of specific extracellular matrix (ECM) proteins in atria, right ventricles and atrioventricular (AV) valves of neonatal and adult mice. Quantification of collagen types I, III and VI and fibronectin was performed using immunofluorescence-labeling and confocal microscopy. Picrosirius red staining was used for the histological assessment of the overall collagen distribution pattern. ECM proteins, metalloproteinases (MMP), ERK1/2 and p38 levels were quantified by western blot analysis. Gelatin zymography was used to evaluate the activity of MMP-2 and MMP-9. We observed that the relative levels of collagen types I and III and fibronectin are significantly higher in both the right ventricle and AV valves of neonatal Mas(-/-) mouse hearts (e.g., collagen type I: 85.28±6.66 vs 43.50±4.41 arbitrary units in the right ventricles of Mas(+/+) mice). Conversely, the level of collagen type VI was lower in the right ventricle and AV valves of Mas(-/-) mice. Adult Mas(-/-) mouse hearts presented similar patterns as observed in neonates. No significant differences in ECM protein level were detected in atria. Likewise, no changes in ECM levels were observed in AT(2) knockout mouse hearts. Although deletion of Mas induced a significant reduction in the level of the active form of MMP-2 in neonate hearts and a reduction of both MMP-2 and MMP-9 in adult Mas(-/-) mice, no significant differences were observed in MMP enzymatic activities when compared to controls. The levels of the active, phosphorylated forms of ERK1/2 and p38 were higher in hearts of both neonatal and adult Mas(-/-) mice. These observations suggest that Mas is involved in the selective expression of specific ECM proteins within both the ventricular myocardium and AV valves. The changes in the ECM profile may alter the connective tissue framework and contribute to the decreased cardiac performance observed in Mas(-/-) mice.

• Renoprotective Effects of AVE0991, a Nonpeptide Mas Receptor Agonist, in Experimental Acute Renal Injury.

  Authors: Lívia Corrêa Barroso, Kátia Daniela Silveira, Cristiano Xavier Lima, Valdinéria Borges, Michael Bader, Milene Rachid, Robson Augusto Souza Santos, Danielle Gloria Souza, Ana Cristina Simões E Silva, Mauro Martins Teixeira

  International journal of hypertension. 01/2012; 2012:808726.

  Renal ischemia and reperfusion (I/R) is the major cause of acute kidney injury in hospitalized patients. Mechanisms underlying reperfusion-associated injury include recruitment and activation ofRenal ischemia and reperfusion (I/R) is the major cause of acute kidney injury in hospitalized patients. Mechanisms underlying reperfusion-associated injury include recruitment and activation of leukocytes and release of inflammatory mediators. In this study, we investigated the renal effects of acute administration of AVE0991, an agonist of Mas, the angiotensin-(1-7) receptor, the angiotensin-(1-7) receptor, in a murine model of renal I/R. Male C57BL/6 wild-type or Mas(-/-) mice were subjected to 30 min of bilateral ischemia and 24 h of reperfusion. Administration of AVE0991 promoted renoprotective effects, as seen by improvement of function, decreased tissue injury, prevention of local and remote leucocyte infiltration, and release of the chemokine, CXCL1. I/R injury was similar in WT and Mas(-/-) mice, suggesting that endogenous activation of this receptor does not control renal damage under baseline conditions. In conclusion, pharmacological interventions using Mas receptor agonists may represent a therapeutic opportunity for the treatment of renal I/R injury.

• Prorenin receptor is essential for podocyte autophagy and survival.

  Authors: Fabian Riediger, Ivo Quack, Fatimunnisa Qadri, Björn Hartleben, Joon-Keun Park, Sebastian A Potthoff, Dennis Sohn, Gabin Sihn, Anthony Rousselle, Verena Fokuhl, Ulrike Maschke, Bettina Purfürst, Wolfgang Schneider, Lars C Rump, Friedrich C Luft, Ralf Dechend, Michael Bader, Tobias B Huber, Genevieve Nguyen, Dominik N Muller

  Journal of the American Society of Nephrology : JASN. 12/2011; 22(12):2193-202.

  The prorenin receptor (PRR) is highly expressed in podocytes, but its role in the maintenance of podocyte function is unknown. Here we generated podocyte-specific PRR-knockout mice and found thatThe prorenin receptor (PRR) is highly expressed in podocytes, but its role in the maintenance of podocyte function is unknown. Here we generated podocyte-specific PRR-knockout mice and found that these animals died between 2 to 3 wk after birth. Within 14 d, PRR-knockout mice developed nephrotic syndrome, albuminuria with podocyte foot-process fusion, and cytoskeletal changes. Podocyte-specific PRR deletion also led to disturbed processing of multivesicular bodies and enrichment of autophagosomal (LC3) and lysosomal (LAMP2) markers, indicating a functional block in autophagosome-lysosome fusion and an overload of the proteasomal protein-degradation machinery. In vitro, PRR knockdown and pharmacologic blockade of vacuolar H(+)-ATPases, which associate with the PRR, increased vesicular pH, led to accumulation of LC3-positive and LAMP2-positive vesicles and altered the cytoskeleton. Taken together, these results suggest that the PRR is essential for podocyte function and survival by maintaining autophagy and protein-turnover machinery. Furthermore, PRR contributes to the control of lysosomal pH, which is important for podocyte survival and cytoskeletal integrity.

• Angiotensin-(1-7) Mas-receptor deficiency decreases peroxisome proliferator-activated receptor gamma expression in adipocytes.

  Authors: Erica Guilhen Mario, Sérgio Henrique S Santos, Adaliene Versiane M Ferreira, Michael Bader, Robson Augusto S Santos, Leida Maria Botion

  Peptides. 11/2011; 33(1):174-7.

  The renin-angiotensin system is an important link between metabolic syndrome and cardiovascular diseases. Besides angiotensin II, other angiotensin peptides such as angiotensin-(1-7), have importantThe renin-angiotensin system is an important link between metabolic syndrome and cardiovascular diseases. Besides angiotensin II, other angiotensin peptides such as angiotensin-(1-7), have important biological activities. It has been demonstrated that angiotensin-(1-7), acting through the G protein-coupled receptor encoded by the Mas protooncogene have important actions on the cardiovascular system. However, the role of angiotensin-(1-7)-Mas axis in lipidic profile is not well established. In the present study, the adipocyte metabolism was investigated in wild type and FVB/N Mas-deficient male mice. The gene expression of peroxisome proliferator-activated receptor gamma, acetyl-CoA carboxylase and the amount of fatty acid synthase protein were reduced in the Mas-knockout mice. Serum nonesterified fatty acids of Mas-knockout showed a 50% increase in relation to wild type group. Basal and isoproterenol-stimulated lipolysis was similar between the groups, however, a significant decrease of the glycerol release (lipolytic index) in response to insulin was observed in wild type animals, while no effect of the insulin action was observed in a Mas-knockout group. The data suggest that the lack of angiotensin-(1-7) action through Mas receptor alters the response of adipocytes to insulin action. These effects might be related to decreased expression of PPARγ.

• Angiotensin-(1-7)/Mas axis integrity is required for the expression of object recognition memory.

  Authors: Thiago L N Lazaroni, Ana Cláudia S Raslan, Walkiria R P Fontes, Marilene L de Oliveira, Michael Bader, Natalia Alenina, Márcio F D Moraes, Robson A Dos Santos, Grace S Pereira

  Neurobiology of learning and memory. 10/2011; 97(1):113-23.

  It has been shown that the brain has its own intrinsic renin-angiotensin system (RAS) and angiotensin-(1-7) (Ang-(1-7)) is particularly interesting, because it appears to counterbalance most of theIt has been shown that the brain has its own intrinsic renin-angiotensin system (RAS) and angiotensin-(1-7) (Ang-(1-7)) is particularly interesting, because it appears to counterbalance most of the Ang II effects. Ang-(1-7) exerts its biological function through activation of the G-protein-coupled receptor Mas. Interestingly, hippocampus is one of the regions with higher expression of Mas. However, the role of Ang-(1-7)/Mas axis in hippocampus-dependent memories is still poorly understood. Here we demonstrated that Mas ablation, as well as the blockade of Mas in the CA1-hippocampus, impaired object recognition memory (ORM). We also demonstrated that the blockade of Ang II receptors AT1, but not AT2, recovers ORM impairment of Mas-deficient mice. Considering that high concentrations of Ang-(1-7) may activate AT1 receptors, nonspecifically, we evaluate the levels of Ang-(1-7) and its main precursors Ang I and Ang II in the hippocampus of Mas-deficient mice. The Ang I and Ang II levels are unaltered in the whole hipocampus of MasKo. However, Ang-(1-7) concentration is increased in the whole hippocampus of MasKo mice, as well as in the CA1 area. Taken together, our findings suggest that the functionality of the Ang-(1-7)/Mas axis is essential for normal ORM processing.

• Mas receptors in modulating relaxation induced by perivascular adipose tissue.

  Authors: Robert M K W Lee, Michael Bader, Natalia Alenina, Robson A S Santos, Yu-Jing Gao, Chao Lu

  Life sciences. 07/2011; 89(13-14):467-72.

  Perivascular adipose tissue (PVAT) is known to secrete vascular relaxation factors, and angiotensin 1-7 [Ang-(1-7)] acting on the endothelium is one of the endothelium-dependent relaxation factors.Perivascular adipose tissue (PVAT) is known to secrete vascular relaxation factors, and angiotensin 1-7 [Ang-(1-7)] acting on the endothelium is one of the endothelium-dependent relaxation factors. Mas protein is the receptor for Ang-(1-7). Using aorta from Mas-knockout (K/O) and wild type (FVB) mice, we wished to establish the essential role of Mas receptors in mediating the endothelium-dependent relaxation response induced by relaxation factors from PVAT. Thoracic aortic rings from K/O and FVB mice were prepared with or without PVAT (PVAT+ and PVAT-) and/or intact endothelium (E+) or with the endothelium removed (E-) for functional studies. The contraction and relaxation responses of these vessels to agonist in the presence of different receptor antagonists were studied. PVAT attenuated the contraction induced by phenylephrine (PHE) in the presence of endothelium only in vessels from FVB mice. Mas receptor antagonists D-Ala-Ang-(1-7) (A779) or D-Pro(7)-Ang-(1-7) enhanced the contraction induced by PHE only in vessels from FVB mice. Ang-(1-7) caused a relaxation response only in E+vessels from FVB mice. Transfer of donor solution from PVAT+ vessels to PVAT- recipient vessels caused a relaxation response among FVB vessels and not among vessels from K/O mice. Mas receptors are essential in mediating the endothelium-dependent relaxation response induced by PVAT, therefore highlighting the important role of Ang-(1-7) in the control of vascular functions through PVAT.

• B1 and B2 kinin receptor participation in hyperproliferative and inflammatory skin processes in mice.

  Authors: Evelise Fernandes Pietrovski, Kátia Sabrina Paludo, Daniel Augusto Gasparin Bueno Mendes, Fernando de Souza Fonseca Guimarães, Silvio Sanchez Veiga, Dorly de Freitas Buchi, Raphael Gomes Fonseca, Aleksander Roberto Zampronio, Michael Bader, João Bosco Pesquero, Juliano Ferreira, Michel Fleith Otuki, Daniela Almeida Cabrini

  Journal of dermatological science. 07/2011; 64(1):23-30.

  Kinins are released during dermal injury and inflammation and seem to contribute to the pathogenesis of cutaneous diseases. Participation of kinins in skin inflammatory process was evaluated usingKinins are released during dermal injury and inflammation and seem to contribute to the pathogenesis of cutaneous diseases. Participation of kinins in skin inflammatory process was evaluated using knockout mice and non-peptide kinin receptor antagonists. Chronic skin inflammation was induced by multiple applications of TPA in mice ear. The B(2) knockout mice (B(2)(-/-)) showed a significant increase of ear weight (23 ± 10%) and epidermal cellular hyperproliferation and acanthosis formation upon histological analysis when compared with wildtype mice. Also, evaluation of PCNA levels by Western blot and immunohistochemistry confirmed the increase in the epidermis hyperproliferation in the ear skin of B(2)(-/-) mice. In contrast, no modification in these parameters was detected in B(1) knockout mice (B(1)(-/-)). However, mice lacking both kinin receptors (B(1)B(2)(-/-)) presented a considerable reduction of epidermis thickness and in PCNA levels. Following the establishment of skin inflammation (5th day of TPA application) treatment with the non-peptide antagonists SSR 240612 (B(1) receptor antagonist), FR 173657 (B(2) receptor antagonist), or SSR 240612 plus FR 173657 topically applied, caused a significant inhibition of ear weight (20 ± 5%, 34 ± 4% and 32 ± 6%, respectively). In the histological analysis, the antagonists produced a reduction in epidermal hyperplasia and acanthosis formation; but the treatment with a combination of the two antagonists did not increase efficacy. Kinin receptors seem to be involved in the control of the keratinocyte hyperproliferative process, and non-peptide kinin receptor antagonists may be useful tools in the treatment of hyperproliferative skin disorders.

• Lrp5 functions in bone to regulate bone mass.

  Authors: Yajun Cui, Paul J Niziolek, Bryan T MacDonald, Cassandra R Zylstra, Natalia Alenina, Daniel R Robinson, Zhendong Zhong, Susann Matthes, Christina M Jacobsen, Ronald A Conlon [......] David R Powell, Qi M Yang, Brian Zambrowicz, Han Gerrits, Jan A Gossen, Xi He, Michael Bader, Bart O Williams, Matthew L Warman, Alexander G Robling

  Nature medicine. 06/2011; 17(6):684-91.

  The human skeleton is affected by mutations in low-density lipoprotein receptor-related protein 5 (LRP5). To understand how LRP5 influences bone properties, we generated mice with osteocyte-specificThe human skeleton is affected by mutations in low-density lipoprotein receptor-related protein 5 (LRP5). To understand how LRP5 influences bone properties, we generated mice with osteocyte-specific expression of inducible Lrp5 mutations that cause high and low bone mass phenotypes in humans. We found that bone properties in these mice were comparable to bone properties in mice with inherited mutations. We also induced an Lrp5 mutation in cells that form the appendicular skeleton but not in cells that form the axial skeleton; we observed that bone properties were altered in the limb but not in the spine. These data indicate that Lrp5 signaling functions locally, and they suggest that increasing LRP5 signaling in mature bone cells may be a strategy for treating human disorders associated with low bone mass, such as osteoporosis.

• Angioprotectin: an angiotensin II-like peptide causing vasodilatory effects.

  Authors: Vera Jankowski, Markus Tölle, Robson A S Santos, Thomas Günthner, Eberhard Krause, Michael Beyermann, Pia Welker, Michael Bader, Sergio Veloso Brant Pinheiro, Walkyria O Sampaio, Roberto Lautner, Axel Kretschmer, Markus van der Giet, Walter Zidek, Joachim Jankowski

  FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 05/2011; 25(9):2987-95.

  The family of angiotensin peptides has been steadily growing in recent years. Most are fragments of angiotensin II (Ang II) with different affinities to the known angiotensin receptors. Here, weThe family of angiotensin peptides has been steadily growing in recent years. Most are fragments of angiotensin II (Ang II) with different affinities to the known angiotensin receptors. Here, we describe a novel endogenous Ang II-like octapeptide in plasma from healthy humans and patients with end-stage renal failure, which acts as a stronger agonist at Mas receptors than Ang 1-7. Chromatographic purification and structural analysis by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF) revealed an Ang II-like octapeptide, angioprotectin, with the sequence Pro-Glu-Val-Tyr-Ile-His-Pro-Phe, which differs from Ang II in Pro¹ and Glu² instead of Asp¹ and Arg². Pro-Glu-Val-Tyr-Ile-His-Pro-Phe in angioprotectin is most likely generated enzymatically from Ang II. Angioprotectin antagonized the contractile actions of Ang II on rat aortic rings. The physiological antagonism of vasoconstrictor actions of Ang II by angioprotectin is mediated by the Mas receptor. Angioprotectin has a stronger affinity to the Mas receptor than Ang-1-7. Plasma concentrations were ~15% of plasma Ang II concentrations in healthy volunteers and up to 50% in patients with renal failure. A commercially available Ang II antibody did not discriminate between angioprotectin and Ang II; thus, angioprotectin can contribute to Ang II concentrations measured by antibody-based assays. This novel peptide is likely to be a relevant component of the human renin-angiotensin-system.

• Effects of electric field on early preimplantation development in vitro in mice and rats.

  Authors: Elena Popova, Michael Bader, Alexander Krivokharchenko

  Human reproduction (Oxford, England). 03/2011; 26(3):662-70.

  Exposure of cells to electric fields is a commonly used technique for parthenogenesis, cloning and tetraploid embryo production. However, little is known about possible detrimental effects ofExposure of cells to electric fields is a commonly used technique for parthenogenesis, cloning and tetraploid embryo production. However, little is known about possible detrimental effects of electric fields on embryos and their development. The aim of this study was to investigate the effects of electric fields on early preimplantation development in mice and rats. Mouse and rat metaphase II (MII) and pre-activated oocytes, zygotes and 2-cell stage embryos were treated with electric fields with increasing voltage. Cleavage rate, morula and blastocyst formation were evaluated by in vitro cultivation. The effects of electric fields on embryos were investigated by measurement of reactive oxygen species (ROS) content and microtubule and microfilament distributions using fluorescence staining. Pre-activated oocytes at the pronuclear stage and zygotes are more resistant to electric exposure than freshly isolated oocytes at MII stage in both studied species. Rat zygotes treated with electric fields of increasing voltage showed higher cleavage rates compared with the mouse and some of them developed beyond 4-cell stage in vitro. Embryos blocked at the 2-cell stage after in vitro cultivation of zygotes exposed to electric fields demonstrated increased level of ROS but normal distributions of microtubules and microfilaments. In both species, embryos at the 2-cell stage were more resistant to electric fields because they formed tetraploid embryos after electric field-induced blastomere fusion and these embryos could develop in vitro until the blastocyst stage. There are stage-dependent and species-specific differences in sensitivity to electric fields in mouse and rats.

• Angiotensin II binding to angiotensin I-converting enzyme triggers calcium signaling.

  Authors: Paola B Guimarães, Érika C Alvarenga, Paula D Siqueira, Edgar J Paredes-Gamero, Regiane A Sabatini, Rafael L T Morais, Rosana I Reis, Edson L Santos, Luis G D Teixeira, Dulce E Casarini [......] Suma I Shimuta, Adriana K Carmona, Clovis R Nakaie, Miriam G Jasiulionis, Alice T Ferreira, Jorge L Pesquero, Suzana M Oliveira, Michael Bader, Claudio M Costa-Neto, João B Pesquero

  Hypertension. 03/2011; 57(5):965-72.

  Angiotensin (Ang) I-converting enzyme (ACE) is involved in the control of blood pressure by catalyzing the conversion of Ang I into the vasoconstrictor Ang II and degrading the vasodilator peptideAngiotensin (Ang) I-converting enzyme (ACE) is involved in the control of blood pressure by catalyzing the conversion of Ang I into the vasoconstrictor Ang II and degrading the vasodilator peptide bradykinin. Human ACE also functions as a signal transduction molecule, and the binding of ACE substrates or its inhibitors initiates a series of events. In this study, we examined whether Ang II could bind to ACE generating calcium signaling. Chinese hamster ovary cells transfected with an ACE expression vector reveal that Ang II is able to bind with high affinity to ACE in the absence of the Ang II type 1 and type 2 receptors and to activate intracellular signaling pathways, such as inositol 1,4,5-trisphosphate and calcium. These effects could be blocked by the ACE inhibitor, lisinopril. Calcium mobilization was specific for Ang II, because other ACE substrates or products, namely Ang 1-7, bradykinin, bradykinin 1-5, and N-acetyl-seryl-aspartyl-lysyl-proline, did not trigger this signaling pathway. Moreover, in Tm5, a mouse melanoma cell line endogenously expressing ACE but not Ang II type 1 or type 2 receptors, Ang II increased intracellular calcium and reactive oxygen species. In conclusion, we describe for the first time that Ang II can interact with ACE and evoke calcium and other signaling molecules in cells expressing only ACE. These findings uncover a new mechanism of Ang II action and have implications for the understanding of the renin-Ang system.

• ACE2-angiotensin-(1-7)-Mas axis and oxidative stress in cardiovascular disease.

  Authors: Luiza A Rabelo, Natalia Alenina, Michael Bader

  Hypertension research : official journal of the Japanese Society of Hypertension. 02/2011; 34(2):154-60.

  The renin-angiotensin-aldosterone system (RAAS) is a pivotal regulator of physiological homeostasis and diseases of the cardiovascular system. Recently, new factors have been discovered, such asThe renin-angiotensin-aldosterone system (RAAS) is a pivotal regulator of physiological homeostasis and diseases of the cardiovascular system. Recently, new factors have been discovered, such as angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) and Mas. This newly defined ACE2-angiotensin-(1-7)-Mas axis was shown to have a critical role in the vasculature and in the heart, exerting mainly protective effects. One important mechanism of the classic and the new RAAS regulate vascular function is through the regulation of redox signaling. Angiotensin II is a classic prooxidant peptide that increases superoxide production through the activation of NAD(P)H oxidases. This review summarizes the current knowledge about the ACE2-angiotensin-(1-7)-Mas axis and redox signaling in the context of cardiovascular regulation and disease. By interacting with its receptor Mas, angiotensin-(1-7) induces the release of nitric oxide from endothelial cells and thereby counteracts the effects of angiotensin II. ACE2 converts angiotensin II to angiotensin-(1-7) and, thus, is a pivotal regulator of the local effects of the RAAS on the vessel wall. Taken together, the ACE2-angiotensin-(1-7)-Mas axis emerges as a novel therapeutic target in the context of cardiovascular and metabolic diseases.

• Local renin-angiotensin system and the brain--a continuous quest for knowledge.

  Authors: Ovidiu C Baltatu, Luciana A Campos, Michael Bader

  Peptides. 02/2011; 32(5):1083-6.

  The ancient renin-angiotensin system (RAS) was discovered more than a hundred years ago by identifying the rate-limiting enzyme of the system and its relevance to blood pressure regulation. FortyThe ancient renin-angiotensin system (RAS) was discovered more than a hundred years ago by identifying the rate-limiting enzyme of the system and its relevance to blood pressure regulation. Forty years ago, Detlev Ganten et al. postulated the existence of a tissue RAS. In these forty years, he kept developing the knowledge of these systems either directly or by training or attracting the interest of many researchers. Through the present review, we try to highlight recent advancements that originated from the postulation of local brain RAS. Although a large amount of knowledge accumulated, this system continues to intrigue and stimulate the interest and imagination of many researchers.

• Brain Renin-Angiotensin system in hypertension, cardiac hypertrophy, and heart failure.

  Authors: Luciana Aparecida Campos, Michael Bader, Ovidiu Constantin Baltatu

  Frontiers in physiology. 01/2011; 2:115.

  Brain renin-angiotensin system (RAS) is significantly involved in the roles of the endocrine RAS in cardiovascular regulation. Our studies indicate that the brain RAS participates in the developmentBrain renin-angiotensin system (RAS) is significantly involved in the roles of the endocrine RAS in cardiovascular regulation. Our studies indicate that the brain RAS participates in the development of cardiac hypertrophy and fibrosis through sympathetic activation. Inhibition of sympathetic hyperactivity after myocardial infarction through suppression of the brain RAS appears beneficial. Furthermore, the brain RAS modulates the cardiovascular and fluid-electrolyte homeostasis not only by interacting with the autonomic nervous system but also by modulating hypothalamic-pituitary axis and vasopressin release. The brain RAS is also involved in the modulation of circadian rhythms of arterial pressure, contributing to non-dipping hypertension. We conclude that the brain RAS in pathophysiological states interacts synergistically with the chronically overactive RAS through a positive biofeedback in order to maintain a state of alert in diseased conditions, such as cardiac hypertrophy and failure. Therefore, targeting brain RAS with drugs such as renin or angiotensin converting enzyme inhibitors or receptor blockers having increased brain penetrability could be of advantage.

• Simulation software for supercomputers.

  Authors: Michael Bader, Miriam Mehl, Ulrich Rüde, Gerhard Wellein

  J. Comput. Science. 01/2011; 2:93-94.

• Derivation, characterization, and stable transfection of induced pluripotent stem cells from Fischer344 rats.

  Authors: Mikhail Liskovykh, Ilya Chuykin, Ashish Ranjan, Dina Safina, Elena Popova, Elena Tolkunova, Valentina Mosienko, Julia M Minina, Natalia S Zhdanova, John J Mullins, Michael Bader, Natalia Alenina, Alexey Tomilin

  PloS one. 01/2011; 6(11):e27345.

  The rat represents an important animal model that, in many respects, is superior to the mouse for dissecting behavioral, cardiovascular and other physiological pathologies relevant to humans.The rat represents an important animal model that, in many respects, is superior to the mouse for dissecting behavioral, cardiovascular and other physiological pathologies relevant to humans. Derivation of induced pluripotent stem cells from rats (riPS) opens the opportunity for gene targeting in specific rat strains, as well as for the development of new protocols for the treatment of different degenerative diseases. Here, we report an improved lentivirus-based hit-and-run riPS derivation protocol that makes use of small inhibitors of MEK and GSK3. We demonstrate that the excision of proviruses does not affect either the karyotype or the differentiation ability of these cells. We show that the established riPS cells are readily amenable to genetic manipulations such as stable electroporation. Finally, we propose a genetic tool for an improvement of riPS cell quality in culture. These data may prompt iPS cell-based gene targeting in rat as well as the development of iPS cell-based therapies using disease models established in this species.

• Differential use of importin-α isoforms governs cell tropism and host adaptation of influenza virus.

  Authors: Gülsah Gabriel, Karin Klingel, Anna Otte, Swantje Thiele, Ben Hudjetz, Gökhan Arman-Kalcek, Martina Sauter, Tatiana Shmidt, Franziska Rother, Sigrid Baumgarte, Björn Keiner, Enno Hartmann, Michael Bader, George G Brownlee, Ervin Fodor, Hans-Dieter Klenk

  Nature communications. 01/2011; 2:156.

  Influenza A viruses are a threat to humans due to their ability to cross species barriers, as illustrated by the 2009 H1N1v pandemic and sporadic H5N1 transmissions. Interspecies transmissionInfluenza A viruses are a threat to humans due to their ability to cross species barriers, as illustrated by the 2009 H1N1v pandemic and sporadic H5N1 transmissions. Interspecies transmission requires adaptation of the viral polymerase to importin-α, a cellular protein that mediates transport into the nucleus where transcription and replication of the viral genome takes place. In this study, we analysed replication, host specificity and pathogenicity of avian and mammalian influenza viruses, in importin-α-silenced cells and importin-α-knockout mice, to understand the role of individual importin-α isoforms in adaptation. For efficient virus replication, the polymerase subunit PB2 and the nucleoprotein (NP) of avian viruses required importin-α3, whereas PB2 and NP of mammalian viruses showed importin-α7 specificity. H1N1v replication depended on both, importin-α3 and -α7, suggesting ongoing adaptation of this virus. Thus, differences in importin-α specificity are determinants of host range underlining the importance of the nuclear envelope in interspecies transmission.