Biology subjects

Chang, G.-J.

Publications and source records attributed to Chang, G.-J..

3 recordsLinked to original sources

bioRxiv2023

Empagliflozin reduces neointimal formation and vascular smooth muscle cell proliferation via the suppression of PDGF-related signaling

ObjectiveEmerging evidence has documented the beneficial effects of sodium glucose cotransporter 2 (SGLT2) inhibitors on reducing cardiovascular events. Beyond glucose regulation, the mechanisms behind their cardioprotective effects still remained unresolved. This study aims to investigate whether these benefits are mediated by their effects on vascular smooth muscle cell (VSMC) functions. Approach and ResultsTreatment of non-diabetic rats with empagliflozin (a SGLT2 inhibitor) attenuated balloon injury-induced neointimal formation in carotid arteries. In vitro, treatment of rat VSMCs with empagliflozin reduced platelet-derived growth factor (PDGF)-BB-induced proliferation and migration. Moreover, empagliflozin-treated VSMCs did not undergo apoptosis and cytosis. Notably, treating VSMCs with empagliflozinsuppressed the activation of PDGF-related signaling, such as that related to the phosphorylation of PDGF receptor b (PDGF-Rb), Akt, and STAT3. Furthermore, overactivation of PDGF-related signaling attenuated the inhibitory effects of empagliflozin on VSMC proliferation and migration. The relevant in vitro findings were corroborated in the neointima of empagliflozin-treated rats. The fact that minimal SGLT2 was discovered in rat VSMCs and SGLT2 silencing did not alter the effect of empagliflozin supported the SGLT2-independent effect of empagliflozin on VSMC functions. ConclusionsThis study highlights the crucial role of PDGF-related signaling in mediating the beneficial effects of empagliflozin on VSMC functions and/or neointimal formation, which are independent of its effects on SGLT2 and glucose metabolism.

molecular biology↗

bioRxiv2021

Istaroxime metabolite PST3093 selectively stimulates SERCA2a and reverses disease-induced changes in cardiac function

BackgroundHeart failure (HF) therapeutic toolkit would strongly benefit from the availability of ino-lusitropic agents with a favorable pharmacodynamics and safety profile. Istaroxime is a promising agent, which combines Na+/K+ pump inhibition with SERCA2a stimulation; however, it has a very short half-life and extensive metabolism to a molecule, named PST3093. The present work aims to investigate whether PST3093, still retains the pharmacodynamic and pharmacokinetic properties of its parent compound. MethodsWe studied PST3093 for its effects on SERCA2a and Na+/K+ ATPase activities, Ca2+ dynamics in isolated myocytes and hemodynamic effects in an in-vivo rat model of diabetic (streptozotocin (STZ)-induced) cardiomyopathy. ResultsIstaroxime infusion in HF patients led to accumulation of PST3093 in the plasma; clearance was substantially slower for PST3093 than for istaroxime. In cardiac rat preparations PST3093 did not inhibit the Na+/K+ ATPase activity, but retained SERCA2a stimulatory activity. In in-vivo echocardiographic assessment, PST3093 improved overall cardiac performance and reversed most STZ-induced abnormalities. PST3093 i.v. toxicity was considerably lower than that of istaroxime and it failed to significantly interact with 50 off-targets. ConclusionsOverall, PST3093 is a "selective" SERCA2a activator, the prototype of a novel pharmacodynamic category with a potential in the ino-lusitropic approach to HF with prevailing diastolic dysfunction. Its pharmacodynamics are peculiar and its pharmacokinetics are suitable to prolong the cardiac beneficial effect of istaroxime infusion. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/455204v3_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@bc9220org.highwire.dtl.DTLVardef@1d7a6eorg.highwire.dtl.DTLVardef@1510c71org.highwire.dtl.DTLVardef@7f037_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2020

Hemodynamic and electromechanical effects of paraquat in rat heart

Paraquat (PQ) is a highly lethal herbicide. Ingestion of large quantities of PQ usually results in cardiovascular collapse and eventually death. However, the mechanism of acute PQ poisoning induced cardiotoxicity is poorly understood. Therefore, the purpose of the present study was to aim to investigate the mechanisms of PQ induced cardiotoxicity by examining the effects of PQ on hemodynamics in vivo, as well as in vitro on isolated hearts and ventricular myocytes in rats. Intravenous administration of PQ (100 or 180 mg/kg) in anesthetized rats induced dose-dependent decreases in heart rate, blood pressure, and cardiac contractility (left ventricular [LV] dP/dtmax). Furthermore, it prolonged the rate-corrected QT (QTc) interval. In Langendorff-perfused isolated hearts, PQ (33 or 60 μM) decreased LV pressure and contractility (LV dP/dtmax in isolated ventricular myocytes), PQ (10–60 μM) decreased the amplitude of Ca2+ transients and cell shortening in a concentration-dependent manner. Patch-clamp experiments demonstrated that PQ decreased the amplitude and availability of the transient outward K+ channel (Ito) and altered its gating kinetics. These results suggest that PQ-induced cardiotoxicity results mainly from diminished Ca2+ transients and inhibited K+ channels, which lead to the suppression of LV contractile force and prolongation of the QTc interval.View Full Text

pharmacology and toxicology↗