Protective Effect of 3-Deazaadenosine in a Rat Model of Lipopolysaccharide-Induced Myocardial Dysfunction

Braun‐Dullaeus, Ruediger C.; Dietrich, Simon; Schoaff, M.; Sedding, Daniel; Leithaeuser, B.; Walker, Gerhard; Seay, Ulrike; Matthias, Reinhard F; Kummer, Wolfgang; Tillmanns, Harald; Haberbosch, Werner

doi:10.1097/00024382-200303000-00008

Cited by 12 publications

(8 citation statements)

References 35 publications

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“…Similarly, an up-regulation of P-selectin within vessels of heart in a rat endotoxin model was previously reported. 22 By immunohistochemistry and cytochemistry, our findings revealed the mechanism of cardiac injury in macaques with early-phase endotoxic shock. We consider that the increase of iNOS, L-selectin and P-selectin expression following LPS injection resulted in the pathogenetic vessels and in lysosomal abnormality, which was an indicator of myocardial injury.…”

Section: Discussionmentioning

confidence: 75%

Early-phase Endotoxic Shock-induced Myocardial Injury Increases iNOS and Selectin Expression in Macaque Primate

Yin

et al. 2007

Heart, Lung and Circulation

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Section: Discussionmentioning

confidence: 75%

Early-phase Endotoxic Shock-induced Myocardial Injury Increases iNOS and Selectin Expression in Macaque Primate

Yin

et al. 2007

Heart, Lung and Circulation

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“…While adenosine analogues and A 2A R agonists can limit endotoxemic or septic injury in lung [15,16], liver [17], brain [18] and heart [19][20][21], the roles of intrinsic A 2A R activity are less clear. Receptor deletion fails to modify inflammatory markers/injury in some studies [22], reportedly worsens endotoxemic injury in heart [23] and lung [15,24] and improves survival in models of polymicrobial sepsis [25,26].…”

Section: J Ashton and Melissa E Reichelt Denotes Equal First Authormentioning

confidence: 99%

“…Endotoxemic cardio-depression Cardiomyocyte and myocardial function is LPS-sensitive and depressed in endotoxemia [21,23,70,71] (Table 1). This has been linked to abnormalities in myofibrillar Ca 2+ sensitivity [70,71], adrenergic control [71][72][73][74] and mitochondrial function [75], together with cell death [23,76,77].…”

Section: Transcriptomic Profile Of Endotoxemic Myocardiummentioning

confidence: 99%

“…While essential genesis of cardiac injury is studied and understood within the in situ organ, this entails experimental limitations inherent to in vivo studies of organ dysfunction in sepsis/ endotoxemia [15,16,20,21,24,41,42,49]. Organ injury in these settings not only involves intrinsic organ-specific mechanisms but also influenced by extrinsic factors, including shifts in systemic inflammation, haemodynamics and neuroendocrine influences (with relative impacts of these factors difficult to delineate).…”

Section: Study Limitationsmentioning

confidence: 99%

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Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

Ashton

Reichelt

Mustafa

et al. 2016

Purinergic Signalling

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Influences of adenosine 2A receptor (A 2A R) activity on the cardiac transcriptome and genesis of endotoxemic myocarditis are unclear. We applied transcriptomic profiling (39 K Affymetrix arrays) to identify A 2A R-sensitive molecules, revealed by receptor knockout (KO), in healthy and endotoxemic hearts. Baseline cardiac function was unaltered and only 37 A 2A R-sensitive genes modified by A 2A R KO (≥1.2-fold change, <5 % FDR); the five most induced are Mtr, Ppbp, Chac1, Ctsk and Cnpy2 and the five most repressed are Hp, Yipf4, Acta1, Cidec and Map3k2. Few canonical paths were impacted, with altered Gnb1, Prkar2b, Pde3b and Map3k2 (among others) implicating modified G protein/cAMP/PKA and cGMP/NOS signalling. Lipopolysaccharide (LPS; 20 mg/kg) challenge for 24 h modified >4100 transcripts in wild-type (WT) myocardium (≥1.5-fold change, FDR < 1 %); the most induced are Lcn2 (+590); Saa3 (+516); Serpina3n (+122); Cxcl9 (+101) and Cxcl1 (+89) and the most repressed are Car3 (−38); Adipoq (−17); Atgrl1/Aplnr (−14); H19 (−11) and Itga8 (−8). Canonical responses centred on inflammation, immunity, cell death and remodelling, with pronounced amplification of tolllike receptor (TLR) and underlying JAK-STAT, NFκB and MAPK pathways, and a 'cardio-depressant' profile encompassing suppressed ß-adrenergic, PKA and Ca 2+ signalling, electromechanical and mitochondrial function (and major shifts in transcripts impacting function/injury including Lcn2, S100a8/S100a9, Icam1/Vcam and Nox2 induction, and Adipoq, Igf1 and Aplnr repression). Endotoxemic responses were selectively modified by A 2A R KO, supporting inflammatory suppression via A 2A R sensitive shifts in regulators of NFκB and JAK-STAT signalling (IκBζ, IκBα, STAT1, CDKN1a and RRAS2) without impacting the cardio-depressant gene profile. Data indicate A 2A Rs exert minor effects in un-stressed myocardium and selectively suppress NFκB and JAK-STATsignalling and cardiac injury without influencing cardiac depression in endotoxemia.

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“…These include thrombinstimulated production of platelet-derived growth factor and the expression of endothelial leukocyte adhesion molecule-1 3 as well as cellular arachidonic acid and ROS production. 4,5 Moreover, c3Ado prevents tumor necrosis factor (TNF)-␣ production, reduces TNF-␣-induced macrophage adhesion to endothelial cells in vitro via the inhibition of ICAM-1 synthesis, and promotes monocyte apoptosis. 6 We recently demonstrated that c3Ado inhibits endothelial expression of ICAM-1 and VCAM-1 in vivo and prevents diet-induced plaque formation in apolipoprotein (apo)E Ϫ/Ϫ mice.…”

mentioning

confidence: 99%

3-Deazaadenosine Prevents Smooth Muscle Cell Proliferation and Neointima Formation by Interfering With Ras Signaling

Sedding

Tröbs

Reich

et al. 2009

Circulation Research

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Abstract-3-Deazaadenosine (c3Ado) is a potent inhibitor of S-adenosylhomocysteine hydrolase, which regulates cellular methyltransferase activity. In the present study, we sought to determine the effect of c3Ado on vascular smooth muscle cell (VSMC) function and neointima formation in vivo. c3Ado dose-dependently prevented the proliferation and migration of human coronary VSMCs in vitro. This was accompanied by an increased expression of the cyclindependent kinase inhibitors p21 WAF1/Cip1 , p27 Kip1 , a decreased expression of G 1 /S phase cyclins, and a lack of retinoblastoma protein hyperphosphorylation. In accordance with these findings, fluorescence-activated cell-sorting analysis of propidium iodide-stained cells indicated a cell cycle arrest in the G 0 /G 1 phase. Importantly, c3Ado did not affect the number of viable (trypan blue exclusion) or apoptotic cells (TUNEL). Mechanistically, c3Ado prevented FCS-induced Ras carboxyl methylation and membrane translocation and activity by inhibiting isoprenylcysteine carboxyl methyltransferase and reduced FCS-induced extracellular signal-regulated kinase (ERK)1/2 and Akt phosphorylation in a dose-dependent manner. Conversely, rescuing signal transduction by overexpression of a constitutive active Ras mutant abrogated c3Ado's effect on proliferation. For in vivo studies, the femoral artery of C57BL/6 mice was dilated and mice were fed a diet containing 150 g of c3Ado per day. c3Ado prevented dilation-induced Ras activation, as well as ERK1/2 and Akt phosphorylation in vivo. At day 21, VSMC proliferation (proliferating-cell nuclear antigen [PCNA]-positive cells), as well as the neointima/media ratio (0.7Ϯ0.2 versus 1.6Ϯ0.4; PϽ0.05) were significantly reduced, without any changes in the number of apoptotic cells. Our data indicate that c3Ado interferes with Ras methylation and function and thereby with mitogenic activation of ERK1/2 and Akt, preventing VSMC cell cycle entry and proliferation and neointima formation in vivo. Thus, therapeutic inhibition of S-adenosylhomocysteine hydrolase by c3Ado may represent a save and effective novel approach to prevent vascular proliferative disease. (Circ Res. 2009;104:1192-1200.) Key Words: neointima formation Ⅲ restenosis Ⅲ signal transduction Ⅲ smooth muscle cells Ⅲ vascular smooth muscle cell proliferation V ascular smooth muscle cell (VSMC) migration, proliferation, and hypertrophy triggered by inflammatory responses of the vessel wall are considered to be key events in the development of atherosclerosis, postangioplasty restenosis, and venous bypass graft failure. 1,2 Consequently, antiinflammatory and antiproliferative 2 strategies have been demonstrated to successfully prevent the development of vascular proliferative disease. Therefore, the identification of novel compounds with combined antiinflammatory/antiproliferative properties holds promise to improve existing therapeutic strategies by limiting late cardiovascular complications like in-stent restenosis or bypass graft failure.3-Deazaadenosine (c3Ado), a structural ...

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Protective Effect of 3-Deazaadenosine in a Rat Model of Lipopolysaccharide-Induced Myocardial Dysfunction

Cited by 12 publications

References 35 publications

Early-phase Endotoxic Shock-induced Myocardial Injury Increases iNOS and Selectin Expression in Macaque Primate

Early-phase Endotoxic Shock-induced Myocardial Injury Increases iNOS and Selectin Expression in Macaque Primate

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

3-Deazaadenosine Prevents Smooth Muscle Cell Proliferation and Neointima Formation by Interfering With Ras Signaling

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