13 research outputs found
Hydromethylthionine rescues synaptic SNARE proteins in a mouse model of tauopathies : interference by cholinesterase inhibitors
The authors acknowledge Malgorzata Wydrych and Joanna Lewandowska for the technical support with perfusion of mice and collection of brains, and of Soumya Palliyil Soman for the development of the s1D12 antibody.Peer reviewe
Differential compartmental processing and phosphorylation of pathogenic human tau and native mouse tau in the Line 66 model of frontotemporal dementia
Funding Information: Funding and additional informationâThis work was supported by EMPIR programme in Research Project 15HLT02 ReMiND cofinanced by the Participating States and the European Union's Horizon 2020 research and innovation programme (to N. L.). Work was also supported by WisTa Laboratories Ltd. (to V. M., D. L., M. M., C. R. H., G. R., C. M. W., F. T., and K. S.). Conflict of interestâThis work was sponsored by WisTa Laboratories Ltd., an affiliate of TauRx Therapeutics Ltd. C. R. H. and C. M. W. are employees and officers of TauRx Therapeutics Ltd.Peer reviewedPublisher PD
Angiotensin Type 2 Receptor Stimulation Ameliorates Left Ventricular Fibrosis and Dysfunction via Regulation of Tissue Inhibitor of Matrix Metalloproteinase 1/Matrix Metalloproteinase 9 Axis and Transforming Growth Factor ÎČ1 in the Rat Heart
Mechanisms of anticholinesterase interference with tau aggregation inhibitor activity in a tau-transgenic mouse model
AVAILABILITY OF DATA AND MATERIALS The data that support the findings of this study are available from the corresponding author [CMW], upon reasonable request. FUNDING This study was sponsored entirely by WisTa Laboratories Ltd. under the following grants: PAR1395, PAR1561, PAR1562, PAR1577 and PAR1763. The sponsor was involved in the design of the study; in the collection, analysis and interpretation of data; and in the writing of the report. The corresponding author had full access to all the data and had final responsibility for submission of the report for publication.Peer reviewedPostprin
PrÀvention eines kardialen Remodelings nach experimentellem Myokardinfarkt. Die Rolle der Angiotensin II Typ 2 Rezeptor Stimulation und der Modulation der MMP/TIMP Achse
This work summarizes our observations on the prevention of cardiac remodelling
after experimental myocardial infarction (MI). MI remains a leading cause of
morbidity and mortality worldwide and hence requires further therapeutic
investigations. In the late phase of MI, adverse post-ischemic cardiac
remodeling is characterized by fibrotic processes, collagen deposition and
extracellular matrix degradation. The cardiac renin-angiotensin-aldosterone
system (RAAS) plays an important role in post-ischemic pathological processes
via AT1 receptor subtype (AT1R) activation. The AT2 receptor (AT2R)
counteracts the AT1R. Therefore, we studied the effects of the AT2R
stimulation by the direct non-peptide agonist C21 in the experimental model of
MI in the rat 6 weeks after coronary artery ligation (P1). Treatment with C21
prevented left ventricular dilatation and dysfunction as evidenced by an
improvement of cardiac systolic and diastolic parameters. Moreover, the AT2R
stimulation decreased interstitial fibrosis and collagen accumulation. The
anti-fibrotic effect was associated with a down-regulation of the pro-fibrotic
cytokine Transforming Growth Factor beta 1 (TGF-ÎČ1) in the heart. Increased
matrix metalloproteinase 9 (MMP9) levels and decreased tissue inhibitor of
metalloproteases 1 (TIMP1) protein evidenced the proteolytic dysbalance. This
dysbalance was ameliorated by C21 by activating TIMP1 which, in turn,
inhibited MMP9. Collectively, these findings provide evidence of
cardioprotective effects of the AT2R stimulation in the late phase post MI.
The second study (P2) investigated the effects of the selective cannabinoid-1
receptor (CB1R) antagonist rimonabant in the rat model of MI and experimental
metabolic syndrome. Blocking of the CB1R improved systolic and diastolic
cardiac functions in the early and late stage after myocardial infarction,
decreased pulse wave reflections and reduced cardiac remodelling. Importantly,
CB1R blockade was also cardioprotective in rats with metabolic syndrome.
Inhibition of proteolysis and decreased collagen accumulation due to reduced
expression of TGF-ÎČ1 are the main mechanisms involved in the protective action
of CB1 receptor blockade in the heart. We have also investigated the role of
the kallikrein-kininogen-kinin system in the regulation of MMPs and TIMPs
(P3). The cleaved form of high molecular weight kininogen (HKa) regulated the
expression of MMP9, MMP2 and TIMPs in vascular smooth muscle cells. HKa
reduced the IL-1α-stimulated release of MMP9 and MMP2.â These results
demonstrate that HKa affects the regulation of MMPs/TIMPs axis. Hence, HKa may
also be a potential drug target for treatment of cardiovascular diseases. In
summary, modulating of cardiac MMPs/TIMPs axis and prevention of TGF-ÎČ1
associated fibrosis obviate left ventricular remodelling and promote
functional improvement after MI.Diese Arbeit fasst unsere Beobachtungen ĂŒber die PrĂ€vention von kardialem
Remodeling nach experimentellem Myokardinfarkt zusammen. Herzinfarkt stellt
die Hauptursache fĂŒr MorbiditĂ€t und MortalitĂ€t weltweit dar und erfordert
weitere therapeutische Untersuchungen. In der SpÀtphase des Herzinfarktes ist
postischÀmisches kardiales Remodeling durch fibrotische Prozesse,
Kollagenablagerung und extrazellulÀre Matrixdegradation gekennzeichnet. Das
kardiale Renin-Angiotensin-Aldosteron-System (RAAS) spielt eine wichtige Rolle
in den postischÀmischen pathologischen Prozessen durch die AT1-Rezeptor-Subtyp
(AT1R) Aktivierung. Der AT2-Rezeptor (AT2R) wirkt dem AT1R entgegen. Daher
untersuchten wir die Effekte der Stimulation mit dem direkten nicht-
peptidischen AT2R-Agonist C21 in einem experimentellen Infarkt-Modell in
Ratten 6 Wochen nach Koronararterien-Ligatur (P1). Die Therapie mit C21 hat
die Dilatation des linken Ventrikels und die Dysfunktion durch eine
Verbesserung der kardialen systolischen und diastolischen Parameter
unterbunden. AuĂerdem verringerte die AT2R Stimulation die interstitielle
Fibrose und Kollagenakkumulation. Die antifibrotische Wirkung war mit einer
Hemmung des pro-fibrotischen Zytokins Transforming growth factor ÎČ1 (TGF-ÎČ1)
im Herzgewebe assoziiert. Erhöhte Matrix-Metalloproteinase 9 (MMP9)-Niveaus
und eine reduzierte Tissue inhibitor of metalloproteases 1 (TIMP1)-Expression
auf Proteinebene belegten die proteolytische Dysbalance im postischÀmischen
Herzgewebe. Dieses Ungleichgewicht wurde mit C21 durch TIMP1-Aktivierung, die
wiederum MMP9 hemmte, verbessert. Zusammenfassend weisen diese Ergebnisse auf
kardioprotektive Wirkungen der AT2R Stimulation in der SpÀtphase des
Myokardinfarkts hin. Die zweite Studie (P2) untersuchte die Effekte des
selektiven Cannabinoid-1-Rezeptor (CB1R) Antagonisten Rimonabant im
Rattenmodell eines MI und eines experimentellen metabolischen Syndroms. Die
Blockade des CB1R verbesserte die systolischen und diastolischen
Herzfunktionen in der frĂŒhen und spĂ€ten Phase nach MI, reduzierte die
Pulswellenreflexionen und das kardiale Remodeling. Wichtig ist, dass die CB1R
Blockade auch kardioprotektiv bei Ratten mit metabolischem Syndrom Wirkung
zeigte.â Die Hemmung der Proteolyse und die verminderte Kollagenakkumulation
durch reduzierte TGF-ÎČ1-Expression stellen die Hauptmechanismen der
Schutzwirkung der CB1-Rezeptor-Blockade im Herz dar. Die Rolle des Kallikrein-
Kininogen-Kinin Systems in der Regulation von MMPs und TIMPs wurde auch
untersucht (P3). Die gespaltene Form von hochmolekularem Kininogen (HKa)
regulierte die Genexpression des MMP9, MMP2 und TIMPs in glatten
GefĂ€Ămuskelzellen. HKa verminderte die IL-1α-stimulierte MMP9 und MMP2-
Freisetzung. Diese Ergebnisse zeigten, dass HKa die MMPs/TIMPs-Achse
moduliert. Daher kann HKa auch als mögliches ZielmolekĂŒl fĂŒr die Behandlung
von kardiovaskulÀren Krankheiten dienen. Zusammenfassend eliminiert die
Modulation der kardialen MMPs/TIMPs-Achse und die PrĂ€vention von TGF-ÎČ1-
assoziierter Fibrose das linksventrikulÀre kardiale Remodeling und fördert die
Funktionsverbesserung nach einem Myokardinfarkt
Clinical and histological presentations of experimental autoimmune myocarditis in rats using different immunization schemes
The (pro)renin receptor mediates constitutive PLZF-independent pro-proliferative effects which are inhibited by bafilomycin but not genistein
The (pro)renin receptor [(P)RR] is crucial for cardio-renal pathophysiology. The distinct molecular mechanisms of this receptor are still incompletely understood. The (P)RR is able to interact with different signalling proteins such as promyelocytic leukemia zinc finger protein (PLZF) and Wnt receptors. Moreover, domains of the (P)RR are essential for V-ATPase activity. V-ATPase- and Wnt-mediated effects imply constitutive, i.e., (pro)renin-independent functions of the (P)RR. Regarding ligand-dependent (P)RR signalling, the role of prorenin glycosylation is currently unknown. Therefore, the aim of this study was to analyse the contribution of constitutive (P)RR activity to its cellular effects and the relevance of prorenin glycosylation on its ligand activity. We were able to demonstrate that high glucose induces (P)RR signal transduction whereas deglycosylation of prorenin abolishes its intrinsic activity in neuronal and epithelial cells. By using siRNA against (P)RR or PLZF as well as the PLZF translocation blocker genistein and the specific V-ATPase inhibitor bafilomycin, we were able to dissect three distinct sub-pathways downstream of the (P)RR. The V-ATPase function is ligand-independently associated with strong pro-proliferative effects whereas prorenin causes moderate proliferation in vitro. In contrast, PLZF per se [i.e., in the absence of (pro)renin] does not interfere with cell number
Cannabinoid receptor 1 inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome
The cannabinoid receptors, CB1 and CB2, are expressed in the heart, but their role under pathological conditions remains controversial. This study examined the effect of CB1 receptor blockade on cardiovascular functions after experimental MI and in experimental metabolic syndrome. MI was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with the CB1 receptor antagonist rimonabant (10 mg/kg i.p. daily) started 7 days before or 6 h after MI and continued for 6 weeks. Haemodynamic parameters were measured via echocardiography and intracardiac Samba catheter. CB1 blockade improved systolic and diastolic heart function, decreased cardiac collagen and hydroxyproline content and down-regulated TGF-beta 1. Additionally, rimonabant decreased arterial stiffness, normalised QRS complex duration and reduced brain natriuretic peptide levels in serum. In primary cardiac fibroblasts, rimonabant decreased MMP-9 activity and TGF-beta 1 expression. Furthermore, rimonabant improved depressed systolic function of spontaneously hypertensive obese rats and reduced weight gain. Blocking of CB1 receptor with rimonabant improves cardiac functions in the early and late stages after MI, decreases arterial stiffness and reduces cardiac remodelling. Rimonabant also has cardioprotective actions in rats characterised by the metabolic syndrome. Inhibition of proteolysis and TGF-beta 1 expression and reduced collagen content by rimonabant may attenuate destruction of the extracellular matrix and decrease fibrosis after MI
Immunoproteasome subunit Ă5i/LMP7-deficiency in atherosclerosis
Abstract Management of protein homeostasis by the ubiquitin-proteasome system is critical for atherosclerosis development. Recent studies showed controversial results on the role of immunoproteasome (IP) subunit ÎČ5i/LMP7 in maintenance of protein homeostasis under cytokine induced oxidative stress. The present study aimed to investigate the effect of ÎČ5i/LMP7-deficiency on the initiation and progression of atherosclerosis as a chronic inflammatory, immune cell driven disease. LDLRâ/âLMP7â/â and LDLRâ/â mice were fed a Western-type diet for either 6 or 24 weeks to induce early and advanced stage atherosclerosis, respectively. Lesion burden was similar between genotypes in both stages. Macrophage content and abundance of polyubiquitin conjugates in aortic root plaques were unaltered by ÎČ5i/LMP7-deficiency. In vitro experiments using bone marrow-derived macrophages (BMDM) showed that ÎČ5i/LMP7-deficiency did not influence macrophage polarization or accumulation of polyubiquitinated proteins and cell survival upon hydrogen peroxide and interferon-Îł treatment. Analyses of proteasome core particle composition by Western blot revealed incorporation of standard proteasome subunits in ÎČ5i/LMP7-deficient BMDM and spleen. Chymotrypsin-, trypsin- and caspase-like activities assessed by using short fluorogenic peptides in BMDM whole cell lysates were similar in both genotypes. Taken together, deficiency of IP subunit ÎČ5i/LMP7 does not disturb protein homeostasis and does not aggravate atherogenesis in LDLRâ/â mice