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Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE161325 | GEO | 2021/07/28

REPOSITORIES: GEO

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Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury [20-0174 RNA-seq]

Project description:While thrombin is the key protease in regard to thrombus formation, other coagulation proteases, such as fXa or activated protein C (aPC), independently modulate intracellular signaling via partially disjunct receptors. Hence, we postulate that inhibition of fXa or fIIa conveys different effects in myocardial ischemia-reperfusion injury (IRI) in regard to inflammation despite comparable anticoagulant efficacy.

2021-07-28 | GSE161324 | GEO

Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury [19-0267 RNA-seq]

2021-07-28 | GSE161323 | GEO

Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury

Project description:Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury

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Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury [19-0267 RNA-seq]

Project description:Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury [19-0267 RNA-seq]

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Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury [20-0174 RNA-seq]

Project description:Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury [20-0174 RNA-seq]

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Theoretical Study of Molecular Structure and Physicochemical Properties of Novel Factor Xa Inhibitors and Dual Factor Xa and Factor IIa Inhibitors.

Project description:The geometries and energies of factor Xa inhibitors edoxaban, eribaxaban, fidexaban, darexaban, letaxaban, and the dual factor Xa and thrombin inhibitors tanogitran and SAR107375 in both the gas-phase and aqueous solution were studied using the Becke3LYP/6-31++G(d,p) or Grimme's B97D/6-31++G(d,p) method. The fully optimized conformers of these anticoagulants show a characteristic l-shape structure, and the water had a remarkable effect on the equilibrium geometry. According to the calculated pKa values eribaxaban and letaxaban are in neutral undissociated form at pH 7.4, while fidexaban and tanogitran exist as zwitterionic structures. The lipophilicity of the inhibitors studied lies within a large range of log P between 1 and 4. The dual inhibitor SAR107375 represents an improvement in structural, physicochemical and pharmacokinetic characteristics over tanogitran. At blood pH, SAR107375 predominantly exists in neutral form. In contrast with tanogitran, it is better absorbed and more lipophilic and active after oral application.

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Spinal cord astrocytes regulate myocardial ischemia-reperfusion injury.

Project description:Astrocytes play a key role in the response to injury and noxious stimuli, but its role in myocardial ischemia-reperfusion (I/R) injury remains largely unknown. Here we determined whether manipulation of spinal astrocyte activity affected myocardial I/R injury and the underlying mechanisms. By ligating the left coronary artery to establish an in vivo I/R rat model, we observed a 1.7-fold rise in glial fibrillary acidic protein (GFAP) protein level in spinal cord following myocardial I/R injury. Inhibition of spinal astrocytes by intrathecal injection of fluoro-citrate, an astrocyte inhibitor, decreased GFAP immunostaining and reduced infarct size by 29% relative to the I/R group. Using a Designer Receptor Exclusively Activated by Designer Drugs (DREADD) chemogenetic approach, we bi-directionally manipulated astrocyte activity employing GFAP promoter-driven Gq- or Gi-coupled signaling. The Gq-DREADD-mediated activation of spinal astrocytes caused transient receptor potential vanilloid 1 (TRPV1) activation and neuropeptide release leading to a 1.3-fold increase in infarct size, 1.2-fold rise in serum norepinephrine level and higher arrhythmia score relative to I/R group. In contrast, Gi-DREADD-mediated inhibition of spinal astrocytes suppressed TRPV1-mediated nociceptive signaling, resulting in 35% reduction of infarct size and 51% reduction of arrhythmia score from I/R group, as well as lowering serum norepinephrine level from 3158 ± 108 to 2047 ± 95 pg/mL. Further, intrathecal administration of TRPV1 or neuropeptide antagonists reduced infarct size and serum norepinephrine level. These findings demonstrate a functional role of spinal astrocytes in myocardial I/R injury and provide a novel potential therapeutic approach targeting spinal cord astrocytes for the prevention of cardiac injury.

| S-EPMC10139732 | biostudies-literature

CaMKII? subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-?B and TNF-?.

Project description:Deletion of Ca2+/calmodulin-dependent protein kinase II delta (CaMKII?) has been shown to protect against in vivo ischemia/reperfusion (I/R) injury. It remains unclear which CaMKII? isoforms and downstream mechanisms are responsible for the salutary effects of CaMKII? gene deletion. In this study we sought to compare the roles of the CaMKII?B and CaMKII?C subtypes and the mechanisms by which they contribute to ex vivo I/R damage. WT, CaMKII?KO, and mice expressing only CaMKII?B or ?C were subjected to ex vivo global ischemia for 25min followed by reperfusion. Infarct formation was assessed at 60min reperfusion by triphenyl tetrazolium chloride (TTC) staining. Deletion of CaMKII? conferred significant protection from ex vivo I/R. Re-expression of CaMKII?C in the CaMKII?KO background reversed this effect and exacerbated myocardial damage and dysfunction following I/R, while re-expression of CaMKII?B was protective. Selective activation of CaMKII?C in response to I/R was evident in a subcellular fraction enriched for cytosolic/membrane proteins. Further studies demonstrated differential regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) signaling and tumor necrosis factor alpha (TNF-?) expression by CaMKII?B and CaMKII?C. Selective activation of CaMKII?C was also observed and associated with NF-?B activation in neonatal rat ventricular myocytes (NRVMs) subjected to oxidative stress. Pharmacological inhibition of NF-?B or TNF-? significantly ameliorated infarct formation in WT mice and those that re-express CaMKII?C, demonstrating distinct roles for CaMKII? subtypes in I/R and implicating acute activation of CaMKII?C and NF-?B in the pathogenesis of reperfusion injury.

| S-EPMC5564300 | biostudies-literature

Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis.

Project description:Intraluminal thrombus is a consistent feature of human abdominal aortic aneurysm (AAA). Coagulation factor Xa (FXa) catalyses FII to thrombin (FIIa). We examined the effect of FXa/FIIa inhibition on experimental aortic aneurysm in apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II (AngII). The concentration of FXa within the supra-renal aorta (SRA) correlated positively with SRA diameter. Parenteral administration of enoxaparin (FXa/IIa inhibitor) and fondaparinux (FXa inhibitor) over 14 days reduced to severity of aortic aneurysm and atherosclerosis in AngII-infused ApoE-/- mice. Enteral administration of the FIIa inhibitor dabigatran had no significant effect. Aortic protease-activated receptor (PAR)-2 expression increased in response to AngII infusion. Fondaparinux reduced SRA levels of FXa, FIIa, PAR-2, matrix metalloproteinase (MMP)2, Smad2/3 phosphorylation, and MOMA-2 positive cells in the mouse model. FXa stimulated Smad2/3 phosphorylation and MMP2 expression in aortic vascular smooth muscle cells (VSMC) in vitro. Expression of MMP2 in FXa-stimulated VSMC was downregulated in the presence of a PAR-2 but not a PAR-1 inhibitor. These findings suggest that FXa/FIIa inhibition limits aortic aneurysm and atherosclerosis severity due to down-regulation of vascular PAR-2-mediated Smad2/3 signalling and MMP2 expression. Inhibition of FXa/FIIa may be a potential therapy for limiting aortic aneurysm.

| S-EPMC5318894 | biostudies-literature

7-Hydroxyflavone Alleviates Myocardial Ischemia/Reperfusion Injury in Rats by Regulating Inflammation.

Project description:Inflammation is the primary pathological process of myocardial ischemia/reperfusion injury (MI/RI). 7-Hydroxyflavone (HF), a natural flavonoid with a variety of bioactivities, plays a crucial role in various biological processes. However, its cardioprotective effects and the underlying mechanisms of MI/RI have not been investigated. This study aimed to explore whether pretreatment with HF could attenuate MI/RI-induced inflammation in rats and investigate its potential mechanisms. The results showed that pretreatment with HF could significantly improve the anatomic data and electrocardiograph parameters, reduce the myocardial infarct size, decrease markers of myocardial injury (aspartate transaminase, creatine kinase, lactate dehydrogenase, and cardiac troponin I), inhibit inflammatory cytokines (IL-1β, IL-6, and TNF-α), suppress oxidative stress, and recover the architecture of the cardiomyocytes. The cardioprotective effect of HF was connected with the regulation of the MAPK/NF-κB signaling pathway. What is more, molecular docking was carried out to prove that HF could be stably combined with p38, ERK1/2, JNK, and NF-κB. In summary, this is a novel study demonstrating the cardioprotective effects of HF against MI/RI in vivo. Consequently, these results demonstrate that HF can be considered a promising potential therapy for MI/RI.

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