Dataset Information

Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair.

ABSTRACT: Herein we investigated a new strategy for the modulation of cardiac macrophages to a reparative state, at a predetermined time after myocardial infarction (MI), in aim to promote resolution of inflammation and elicit infarct repair. The strategy employed intravenous injections of phosphatidylserine (PS)-presenting liposomes, mimicking the anti-inflammatory effects of apoptotic cells. Following PS-liposome uptake by macrophages in vitro and in vivo, the cells secreted high levels of anti-inflammatory cytokines [transforming growth factor ? (TGF?) and interleukin 10 (IL-10)] and upregulated the expression of the mannose receptor--CD206, concomitant with downregulation of proinflammatory markers, such as tumor necrosis factor ? (TNF?) and the surface marker CD86. In a rat model of acute MI, targeting of PS-presenting liposomes to infarct macrophages after injection via the femoral vein was demonstrated by magnetic resonance imaging (MRI). The treatment promoted angiogenesis, the preservation of small scars, and prevented ventricular dilatation and remodeling. This strategy represents a unique and accessible approach for myocardial infarct repair.

SUBMITTER: Harel-Adar T

PROVIDER: S-EPMC3033268 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair.

Harel-Adar Tamar T Ben Mordechai Tamar T Amsalem Yoram Y Feinberg Micha S MS Leor Jonathan J Cohen Smadar S

Proceedings of the National Academy of Sciences of the United States of America 20110118 5

Herein we investigated a new strategy for the modulation of cardiac macrophages to a reparative state, at a predetermined time after myocardial infarction (MI), in aim to promote resolution of inflammation and elicit infarct repair. The strategy employed intravenous injections of phosphatidylserine (PS)-presenting liposomes, mimicking the anti-inflammatory effects of apoptotic cells. Following PS-liposome uptake by macrophages in vitro and in vivo, the cells secreted high levels of anti-inflamma ...[more]

PMID: 21245355

Similar Datasets

Project description:Proper selection and effective delivery of combination drugs targeting multiple pathophysiological pathways key to spinal cord injury (SCI) hold promise to address the thus far scarce clinical therapeutics for improving recovery after SCI. In this study, we aim to develop a clinically feasible way for targeted delivery of multiple drugs with different physiochemical properties to the SCI site, detail the underlying mechanism of neural recovery, and detect any synergistic effect related to combination therapy. Methods: Liposomes (LIP) modified with a scar-targeted tetrapeptide (cysteine-alanine-glutamine-lysine, CAQK) were first constructed to simultaneously encapsulate docetaxel (DTX) and brain-derived neurotrophic factor (BDNF) and then were further added into a thermosensitive heparin-modified poloxamer hydrogel (HP) with affinity-bound acidic fibroblast growth factor (aFGF-HP) for local administration into the SCI site (CAQK-LIP-GFs/DTX@HP) in a rat model. In vivo fluorescence imaging was used to examine the specificity of CAQK-LIP-GFs/DTX binding to the injured site. Multiple comprehensive evaluations including biotin dextran amine anterograde tracing and magnetic resonance imaging were used to detect any synergistic effects and the underlying mechanisms of CAQK-LIP-GFs/DTX@HP both in vivo (rat SCI model) and in vitro (primary neuron). Results: The multiple drugs were effectively delivered to the injured site. The combined application of GFs and DTX supported neuro-regeneration by improving neuronal survival and plasticity, rendering a more permissive extracellular matrix environment with improved regeneration potential. In addition, our combination therapy promoted axonal regeneration via moderation of microtubule function and mitochondrial transport along the regenerating axon. Conclusion: This novel multifunctional therapeutic strategy with a scar-homing delivery system may offer promising translational prospects for the clinical treatment of SCI.

Project description:AIMS:The WNT/?-catenin pathway is temporarily activated in the heart following myocardial infarction (MI). Despite data from genetic models indicating both positive and negative roles for the WNT pathway depending on the model used, the effect of therapeutic inhibition of WNT pathway on post-injury outcome and the cellular mediators involved are not completely understood. Using a newly available, small molecule, GNF-6231, which averts WNT pathway activation by blocking secretion of all WNT ligands, we sought to investigate whether therapeutic inhibition of the WNT pathway temporarily after infarct can mitigate post injury cardiac dysfunction and fibrosis and the cellular mechanisms responsible for the effects. METHODS AND RESULTS:Pharmacologic inhibition of the WNT pathway by post-MI intravenous injection of GNF-6231 in C57Bl/6 mice significantly reduced the decline in cardiac function (Fractional Shortening at day 30: 38.71 ± 4.13% in GNF-6231 treated vs. 34.89 ± 4.86% in vehicle-treated), prevented adverse cardiac remodeling, and reduced infarct size (9.07 ± 3.98% vs. 17.18 ± 4.97%). WNT inhibition augmented proliferation of interstitial cells, particularly in the distal myocardium, inhibited apoptosis of cardiomyocytes, and reduced myofibroblast proliferation in the peri-infarct region. In vitro studies showed that WNT inhibition increased proliferation of Sca1+ cardiac progenitors, improved survival of cardiomyocytes, and inhibited collagen I synthesis by cardiac myofibroblasts. CONCLUSION:Systemic, temporary pharmacologic inhibition of the WNT pathway using an orally bioavailable drug immediately following MI resulted in improved function, reduced adverse remodeling and reduced infarct size in mice. Therapeutic WNT inhibition affected multiple aspects of infarct repair: it promoted proliferation of cardiac progenitors and other interstitial cells, inhibited myofibroblast proliferation, improved cardiomyocyte survival, and reduced collagen I gene expression by myofibroblasts. Our data point to a promising role for WNT inhibitory therapeutics as a new class of drugs to drive post-MI repair and prevent heart failure.

Dataset Information

Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair.

Publications

Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets