Acute DNase1 treatment improves left ventricular remodeling after myocardial infarction by disruption of free chromatin

Vogel, Benjamin; Shinagawa, Hisahito; Hofmann, Ulrich; Ertl, Georg; Frantz, Stefan

doi:10.1007/s00395-015-0472-y

Cited by 40 publications

(31 citation statements)

References 40 publications

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“…Histones released from necrotic cells accumulate within the myocardium early after myocardial infarction (MI), 55 inducing further dose-dependent myocardiocyte toxicity. NET-derived nucleosomes are also implicated in driving inflammatory signalling after cardiac ischaemia and are released via NETosis.…”

Section: Extracellular Histone In Acute Organ Injurymentioning

confidence: 99%

“…Targeting the release of histone complexes and, in particular, inhibiting NETosis has demonstrated considerable specificity and efficacy when used in animal models of AOI 55, 56, 60 and sepsis. 101 Specific PAD4 inhibitors prevent the citrullination of H3, a key step in releasing nucleosomic material for NET formation, 102 and are more effective than DNase1 in preventing tissue damage.…”

Section: Novel Approaches For Targeting Histonementioning

confidence: 99%

“…103 DNase1 theoretically disperses DNA-bound-histone, and hence, reduced NET-mediated cytotoxicity. 55 but are unlikely to be able to effectively access DNase1 binding sites within multifarious NET complexes.…”

Section: Novel Approaches For Targeting Histonementioning

confidence: 99%

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The role of extracellular histone in organ injury

et al. 2017

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Histones are intra-nuclear cationic proteins that are present in all eukaryotic cells and are highly conserved across species. Within the nucleus, they provide structural stability to chromatin and regulate gene expression. Histone may be released into the extracellular space in three forms: freely, as a DNA-bound nucleosome or as part of neutrophil extracellular traps, and all three can be detected in serum after significant cellular death such as sepsis, trauma, ischaemia/reperfusion injury and autoimmune disease. Once in the extracellular space, histones act as damage-associated molecular pattern proteins, activating the immune system and causing further cytotoxicity. They interact with Toll-like receptors (TLRs), complement and the phospholipids of cell membranes inducing endothelial and epithelial cytotoxicity, TLR2/TLR4/TLR9 activation and pro-inflammatory cytokine/chemokine release via MyD88, NFκB and NLRP3 inflammasome-dependent pathways. Drugs that block the release of histone, neutralise circulating histone or block histone signal transduction provide significant protection from mortality in animal models of acute organ injury but warrant further research to inform future clinical applications.

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Section: Extracellular Histone In Acute Organ Injurymentioning

confidence: 99%

Section: Novel Approaches For Targeting Histonementioning

confidence: 99%

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The role of extracellular histone in organ injury

et al. 2017

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“…The attenuation of NA-induced tissue injury has also been attempted with DNase, RNase, small chemicals, and TLR inhibitors 7, 8, 26-31. These agents, however, have short serum half-lives, need to be administered frequently and at a high dose, and are costly.…”

Section: Discussionmentioning

confidence: 99%

Theranostic Nucleic Acid Binding Nanoprobe Exerts Anti-inflammatory and Cytoprotective Effects in Ischemic Injury

Chen¹,

Yuan²,

Cho³

et al. 2017

Theranostics

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Extracellular nucleic acids are proinflammatory molecules that have been implicated in a diverse range of diseases. We report here the development of a multivalent nucleic acid scavenging nanoprobe, where the fluorochrome thiazole orange (TO) is conjugated to a polymeric 40 kDa dextran carrier. Dextran-TO (Dex-TO) has nanomolar affinity for mammalian and bacterial nucleic acids and attenuates the production of inflammatory cytokines from activated macrophages exposed to DNA and RNA. Mice with myocardial ischemia reperfusion that were treated with Dex-TO showed a decrease in myocardial macrophage infiltration at 24 hours (p<0.05) and a decrease in infarct size (18% ± 9%, p<0.01) on day 7. Dex-TO allows sites of injury to be identified with fluorescence imaging, while simultaneously exerting an anti-inflammatory and cytoprotective effect. Dex-TO could be of significant diagnostic and therapeutic (theranostic) utility in a broad range of conditions including ischemia, trauma, burns, sepsis and autoimmune disease.

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“…As described above, NETosis is the formation of extracellular traps from the nuclear release of neutrophils, resulting in the presence of histones in the extracellular space. Studies have shown that inhibiting or removing the PAD4 enzyme in various animal models led to increased survival (62,(86)(87)(88). The limitation of this treatment is the potential for off-target consequences of PAD4 disrupting the innate immune system (89).…”

Section: Current Therapeutics For Multiple Organ Dysfunction Caused Bmentioning

confidence: 99%

Detection and treatment of critical illnesses using oligonucleotides

Urak¹

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Sepsis is among the most prevalent diagnosed critical illnesses in the United States today. Although advances have reduced the overall morbidity and mortality associated with this illness, the enormous number of deaths associated with it shows a need for improved diagnostic and therapeutic options. Our laboratory has utilized RNA based technologies to aid in the treatment of histone induced multiple organ dysfunction syndrome seen in sepsis.Histones are proteins found in the nucleus of every cell in our body and have been shown to be released during sepsis. Such release induces damage to other cells, causing a feed forward cycle that results in organ failure and death. Several therapeutics have been utilized to neutralize histones but have shown considerable toxicity. This thesis describes the generation of single stranded RNA aptamers to bind and neutralize histone mediate damage without unwanted toxicity. We demonstrate that our aptamers selectively bind to histones but not serum proteins. In addition, we establish that our aptamers can neutralize all histone mediated cellular response in vitro and in vivo. Finally, we determined that our aptamers are able inhibit the histone feed forward cycle in a temporal fashion in our murine model of multiple organ dysfunction. This novel therapeutic demonstrates the selectivity and effectiveness needed to inhibit histones in several critical illnesses. iv PUBLIC ABSTRACTThe most prevalent diagnosed critical illness in the western hemisphere is sepsis.Despite recent advances in treatments, the number of deaths associated with sepsis continues to grow, resulting in the need for improved diagnostic and therapeutic options.Our laboratory has utilized RNA based technologies to aid in the treatment and detection of the critical illness stated above.During a critical illness such as sepsis, cells are damaged causing the release of proteins from the nucleus (i.e. histones) resulting in further cellular damage that leads to organ failure and death. To date, one FDA approved therapeutic has been utilized to neutralize histones but resulted in considerable toxicity in the patients. In this thesis we describe a novel therapeutic (single-stranded RNA aptamers) to bind and neutralize histone mediated damage without the toxic side-effects. This novel therapeutic demonstrates the selectivity and efficacy needed to inhibit histones in several critical illnesses.

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Acute DNase1 treatment improves left ventricular remodeling after myocardial infarction by disruption of free chromatin

Cited by 40 publications

References 40 publications

The role of extracellular histone in organ injury

The role of extracellular histone in organ injury

Theranostic Nucleic Acid Binding Nanoprobe Exerts Anti-inflammatory and Cytoprotective Effects in Ischemic Injury

Detection and treatment of critical illnesses using oligonucleotides

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