The effects of the selective sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in low dose on cardiac function were investigated in normoglycemic rats. Cardiac parameters were measured by intracardiac catheterization 30 min after intravenous application of empagliflozin to healthy animals. Empagliflozin increased the ventricular systolic pressure, mean pressure, and the max dP/dt (p < 0.05). Similarly, treatment with empagliflozin (1 mg/kg, p.o.) for one week increased the cardiac output, stroke volume, and fractional shortening (p < 0.05). Myocardial infarction (MI) was induced by ligation of the left coronary artery. On day 7 post MI, empagliflozin (1 mg/kg, p.o.) improved the systolic heart function as shown by the global longitudinal strain (−21.0 ± 1.1% vs. −16.6 ± 0.7% in vehicle; p < 0.05). In peri-infarct tissues, empagliflozin decreased the protein expression of matrix metalloproteinase 9 (MMP9) and favorably regulated the cardiac transporters sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and sodium hydrogen exchanger 1 (NHE1). In H9c2 cardiac cells, empagliflozin decreased the MMP2,9 activity and prevented apoptosis. Empagliflozin did not alter the arterial stiffness, blood pressure, markers of fibrosis, and necroptosis. Altogether, short-term treatment with low-dose empagliflozin increased the cardiac contractility in normoglycemic rats and improved the systolic heart function in the early phase after MI. These effects are attributed to a down-regulation of MMP9 and NHE1, and an up-regulation of SERCA2a. This study is of clinical importance because it suggests that a low-dose treatment option with empagliflozin may improve cardiovascular outcomes post-MI. Down-regulation of MMPs could be relevant to many remodeling processes including cancer disease.
Cannabinoids (CB) are implicated in cardiovascular diseases via the two main receptor subtypes CB1R and CB2R. This study investigated whether cannabinoids regulate the activity of matrix metalloproteases (MMP-2, MMP-9) in vascular smooth muscle cells (VSMCs) and in cells of cardiac origin (H9c2 cell line). The influence of CB1- and CB2 receptor stimulation or inhibition on cell proliferation, apoptosis and glucose uptake was also evaluated. We used four compounds that activate or block CB receptors: arachidonyl-2-chloroethylamide (ACEA)—CB1R agonist, rimonabant—CB1R antagonist, John W. Huffman (JWH133)—CB2R agonist and CB2R antagonist—6-Iodopravadoline (AM630). Treatment of cells with the CB2R agonist JWH133 decreased cytokine activated secretion of proMMP-2, MMP-2 and MMP-9, reduced Fas ligand and caspase-3-mediated apoptosis, normalized the expression of TGF-beta1 and prevented cytokine-induced increase in glucose uptake into the cell. CB1R inhibition with rimonabant showed similar protective properties as the CB2R agonist JWH133, but to a lesser extent. In conclusion, CB1R and CB2R exert opposite effects on cell glucose uptake, proteolysis and apoptosis in both VSMCs and H9c2 cells. The CB2R agonist JWH133 demonstrated the highest protective properties. These findings may pave the way to a new treatment of cardiovascular diseases, especially those associated with extracellular matrix degradation.
Anmerkungen zu einer erinnerungskulturellen "Leerstelle" Dass es sich bei den Speziallagern, die der sowjetische Geheimdienst NKVD mit Ende des Zweiten Weltkriegs auf dem Gebiet der sowjetischen Besatzungszone und späteren DDR errichtete, noch heute um einen "leeren" Erinnerungsort handelt, zeigt sich nirgends deutlicher als in der Belletristik. So finden sich in der Literatur ostdeutscher Autoren allenfalls wie bei Brigitte Reimann Andeutungen auf das sowjetische Lagersystem. 1 "Alles, was uns in diesen Jahren [nach 1945, B.G.] Angst gemacht hat", schreibt der Schriftsteller Günter de Bruyn über seine Themenwahl in Abhängigkeit von der Zensur, "war tabuisiert. Kein Sowjetsoldat durfte in Deutschland geplündert und vergewaltigt haben, kein nach dem Krieg Internierter in Buchenwald, Ketschendorf oder Sibirien verendet sein." 2 Doch auch in der westdeutschen Belletristik hat die stalinistische Verfolgung auf dem Gebiet der SBZ/DDR keine "Schmerzensspur" hinterlassen, um W.G. Sebalds Diktum über die "Leerstelle" des Luftkriegs in der Literatur aufzugreifen. 3 Zwar wurde Sebalds Einschätzung umgehend widerlegt, für die Gewalterfahrung der Speziallagerhaft aber trifft sie ins Schwarze: Heinrich Cresspahl, Protagonist in Uwe Johnsons Jahrestage (1973), war für Jahrzehnte die einzige literarische Figur, deren Geschichte teilweise in einem solchen Lager spielt. 4 Es dauerte mehr als 30 Jahre, bis ihm 2004 mit den beiden Berliner Schulfreunden Paul Scholz und Julian Sternberg zwei fiktive Häftlinge an die Seite gestellt wurden-in dem Jugend buch "Julians Bruder" von Klaus Kordon. 5 Mit diesem Beispiel aus der Belletristik ist auch angezeigt, dass es in der alten Bundesrepublik keiner repressiven Geschichtspolitik wie in der DDR bedurfte, um die massiven Verfolgungserfahrungen dieser Opfergruppe unsichtbar zu machen-und dass sich an dieser Unsichtbarkeit und damit Randständigkeit des Themas innerhalb der nunmehr gesamtdeutschen Erinnerungskultur wenig geändert hat. 6 Jenseits unmittelbar Betroffener und ihrer Angehörigen ist das Wissen um die Gewalt, die horrenden Todeszahlen in den Lagern und den schmalen 1 So in Brigitte Reimanns 1974 posthum in der DDR erschienenen Roman "Franziska Linker hand". Dort heißt es über zwei Bekannte des Vaters Linkerhand: "Der eine ist später an der Ostfront gefallen. Der andere wurde gleich nach der Kapitulation von der GPU verhaftet und starb im Lager."
Objectives Cannabinoid receptors CB1R and CB2R are expressed in the vascular smooth muscle cells (VSMCs) and may contribute to vascular remodeling process (O’Sullivan, 2015). This study aimed to investigate the implication of CB1R and CB2R in the regulation of matrix metalloproteases MMP2 and MMP9, cell proliferation and apoptosis. Methods Primary VSMCs of contractile type were derived from rat aorta. Following compounds were studied: the CB1R agonist arachidonyl-2-chloroethylamide (ACEA), the CB1R antagonist/inverse agonist rimonabant, the CB2R agonist JWH133, the CB2R antagonist/inverse agonist AM630. The cells were treated with compounds simultaneously with IL1α stimulation. MMP2 and MMP9 were analyzed 48h after treatment via gelatin zymography, Western blotting and immunofluorescence. Apoptotic markers FasL, Caspase-3 and TGFbeta1 were used. This experimental setup was repeated using IncuCyte cell imaging to evaluate cell proliferation and apoptosis. Results The CB2R agonist JWH133 decreased the activity of proMMP9 (p < 0.05), abolished IL1α -induced up-regulation of proMMP9/MMP9 proteins, and decreased MMP2 activity by tendency (11%). JWH133 also decreased the number of apoptotic cells (p < 0.05). Accordingly, CB2R antagonist AM630 did not prevent MMP9 release. CB1R antagonist Rimonabant reduced activity of proMMP9 (35%) and MMP2 (4%) and abolished protein up-regulation of proMMP9/MMP9. CB1R stimulation with ACEA had an ambiguous effect. JWH133 and Rimonabant increased cell proliferation (p < 0,05) and decreased expression of apoptosis markers FasL and caspase-3. Conclusions The CB2R agonist JWH133 and CB1R antagonist Rimonabant prevented release of MMP9 and cell death of VSMCs. Therefore, stimulation of the CB2R or blockade of the CB1R may be favorable by vascular outward remodeling processes.
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