Targeting TLR4 with ApTOLL Improves Heart Function in Response to Coronary Ischemia Reperfusion in Pigs Undergoing Acute Myocardial Infarction

Ramírez-Carracedo, Rafael; Tesoro, Laura; Hernández, Ignacio; Díez-Mata, Javier; Piñeiro, David; Hernández-Jiménez, Macarena; Zamorano, José Luís; Zaragoza, Carlos

doi:10.3390/biom10081167

Cited by 25 publications

(27 citation statements)

References 39 publications

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“…The interaction between CCR1 and MCHR 1 (melanin-concentrating hormone receptor 1) was upregulated in the adipose tissue, which promoted fat accumulation ( Kring et al, 2008 ). However, the activation of CCR1 inhibited the expression of CXCL 11 (C–X–C motif chemokine 11) and consequently alleviated heart inflammation ( Ramirez-Carracedo et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Multiple-Tissue and Multilevel Analysis on Differentially Expressed Genes and Differentially Correlated Gene Pairs for HFpEF

et al. 2021

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Heart failure with preserved ejection fraction (HFpEF) is a complex disease characterized by dysfunctions in the heart, adipose tissue, and cerebral arteries. The elucidation of the interactions between these three tissues in HFpEF will improve our understanding of the mechanism of HFpEF. In this study, we propose a multilevel comparative framework based on differentially expressed genes (DEGs) and differentially correlated gene pairs (DCGs) to investigate the shared and unique pathological features among the three tissues in HFpEF. At the network level, functional enrichment analysis revealed that the networks of the heart, adipose tissue, and cerebral arteries were enriched in the cell cycle and immune response. The networks of the heart and adipose tissues were enriched in hemostasis, G-protein coupled receptor (GPCR) ligand, and cancer-related pathway. The heart-specific networks were enriched in the inflammatory response and cardiac hypertrophy, while the adipose-tissue-specific networks were enriched in the response to peptides and regulation of cell adhesion. The cerebral-artery-specific networks were enriched in gene expression (transcription). At the module and gene levels, 5 housekeeping DEGs, 2 housekeeping DCGs, 6 modules of merged protein–protein interaction network, 5 tissue-specific hub genes, and 20 shared hub genes were identified through comparative analysis of tissue pairs. Furthermore, the therapeutic drugs for HFpEF-targeting these genes were examined using molecular docking. The combination of multitissue and multilevel comparative frameworks is a potential strategy for the discovery of effective therapy and personalized medicine for HFpEF.

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Section: Resultsmentioning

confidence: 99%

Multiple-Tissue and Multilevel Analysis on Differentially Expressed Genes and Differentially Correlated Gene Pairs for HFpEF

et al. 2021

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“…We detected a total of 36 human cytokines, chemokines, and acute phase proteins simultaneously from the serum of pigs and mice at the times indicated, by using the Proteome Pro ler Cytokine Array Kit (RD Systems, Minneapolis, MN) a membrane-based antibody array for the parallel determination of the relative levels of selected human cytokines and chemokines, as described [9].…”

Section: Cytokine and Chemokine Determinationsmentioning

confidence: 99%

“…Even though in ammation is a critical component of tissue healing, currently more contributions point towards a prolonged in ammatory response can compromise myocardial structure and function due to an adverse left ventricle remodelling, causing HF [6][7][8]. Therefore, targeting the in ammatory response may represent a promising strategy to prevent adverse outcomes after AMI [9].…”

Section: Introductionmentioning

confidence: 99%

TITTLE: Cardioprotective Effect of New NIL10 Nanoparticles Through IL10 Receptor/STAT3 Activation in Mice and Pigs Subjected Acute Myocardial Infarction

Tesoro

Botana

Ramírez-Carracedo

et al. 2022

Preprint

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Rationale: Early response after acute myocardial infarction (AMI) is crucial to prevent extensive cardiac necrosis. Interleukin-10 (IL-10) is a key antiinflammatory cytokine, whose expression is closely associated with macrophage polarization towards inflammation resolution. Results: We synthesized NIL10, a micelle-based nanoparticle conjugated to IT9302, a peptide homologue to IL-10 functional domain, with the aim of targeting IL-10 receptor in mice and pigs subjected to AMI. Intravenous administration of 1 mg/kg NIL10 improved the cardiac function of mice and pigs subjected to AMI, as shown by a significant recovery of the left ventricle ejection fraction (LVEF) by days 3 and 7 after AMI, when compared to the levels found in animals injected with NIL10SC, a nanoparticle conjugated with the peptide in a scrambled orientation, in which inflammatory foci and fibrosis were strongly elevated. In IL-10 null mice subjected to AMI, NIL10 also improved heart contractility, while in IL10 receptor deficient animals, NIL10 had no effect. To test whether NIL10 may induce macrophage polarization, M2 macrophage populations were increased after day 3 of reperfusion, in which anti-inflammatory cytokines, including IL4, IL7, IL10, IL13, IL16 and IL27 were also elevated in mice and pigs injected with NIL10. Mechanistically, NIL10 induced activation of the IL-10 receptor/STAT-3 signaling pathway, and STAT3-dependent inhibition of pro-inflammatory NF-kB transcription factor nuclear translocation, as evidenced by inhibition of nuclear p65 in macrophages stimulated with 500 mM LPS in response to incubation with NIL10, and prevented by co-incubation with the STAT-3 pharmacological inhibitor STATTIC, as also evidenced by testing the NF-kB -dependent readout iNOS gene expression with same results. Conclusions: Our findings propose NIL10 nanoparticles as a novel compound to improve cardiac function after myocardial infarction, to preventing cardiac necrosis by inducing polarization toward M2-resolving macrophages, through inhibition of STAT3-induced nuclear translocation of NF-kB.

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“…Yorkshire female pigs (37.8 ± 5.2 kg) were subjected to cardiac ischemia/reperfusion as previously described [11].…”

Section: Cardiac Ischemia/reperfusionmentioning

confidence: 99%

“…Proteolysis of the extracellular matrix leads to cardiac necrosis during the onset and progression of myocardial infarction. Among others, Extracellular Matrix Metalloproteases (MMPS), and the MMP inducer EMMPRIN, play a significant role in myocardial infarction [11]. However, MMPs and EMMPRIN are also cargo components of many MVs involved in the migration and proliferation of several cancer and epithelial cells [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Ivabradine-Stimulated Microvesicle Release Induces Cardiac Protection against Acute Myocardial Infarction

Ramírez-Carracedo

Tesoro

Hernández

et al. 2020

IJMS

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Ivabradine can reduce heart rate through inhibition of the current I(f) by still unexplored mechanisms. In a porcine model of ischemia reperfusion (IR), we found that treatment with 0.3 mg/kg Ivabradine increased plasma release of microvesicles (MVs) over Placebo, as detected by flow cytometry of plasma isolated from pigs 7 days after IR, in which a tenfold increase of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) containing (both high and low-glycosylated) MVs, was detected in response to Ivabradine. The source of MVs was investigated, finding a 37% decrease of CD31+ endothelial cell derived MVs, while CD41+ platelet MVs remained unchanged. By contrast, Ivabradine induced the release of HCN4+ (mostly cardiac) MVs. While no differences respect to EMMPRIN as a cargo component were found in endothelial and platelet derived MVs, Ivabradine induced a significant release of EMMPRIN+/HCN4+ MVs by day 7 after IR. To test the role of EMMPRIN+ cardiac MVs (EMCMV), H9c2 cell monolayers were incubated for 24 h with 107 EMCMVs, reducing apoptosis, and increasing 2 times cell proliferation and 1.5 times cell migration. The in vivo contribution of Ivabradine-induced plasma MVs was also tested, in which 108 MVs isolated from the plasma of pigs treated with Ivabradine or Placebo 7 days after IR, were injected in pigs under IR, finding a significant cardiac protection by increasing left ventricle ejection fraction and a significant reduction of the necrotic area. In conclusion ivabradine induces cardiac protection by increasing at least the release of EMMPRIN containing cardiac microvesicles.

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Targeting TLR4 with ApTOLL Improves Heart Function in Response to Coronary Ischemia Reperfusion in Pigs Undergoing Acute Myocardial Infarction

Cited by 25 publications

References 39 publications

Multiple-Tissue and Multilevel Analysis on Differentially Expressed Genes and Differentially Correlated Gene Pairs for HFpEF

Multiple-Tissue and Multilevel Analysis on Differentially Expressed Genes and Differentially Correlated Gene Pairs for HFpEF

TITTLE: Cardioprotective Effect of New NIL10 Nanoparticles Through IL10 Receptor/STAT3 Activation in Mice and Pigs Subjected Acute Myocardial Infarction

Ivabradine-Stimulated Microvesicle Release Induces Cardiac Protection against Acute Myocardial Infarction

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