Targeting and modulating infarct macrophages with hemin formulated in designed lipid-based particles improves cardiac remodeling and function

Ben-Mordechai, Tamar; Kain, David; Holbová, Radka; Landa, Natalie; Levin, La-Paz; Elron-Gross, Inbar; Glucksam-Galnoy, Yifat; Feinberg, Micha S.; Margalit, Rimona; Leor, Jonathan

doi:10.1016/j.jconrel.2017.01.001

Cited by 37 publications

(19 citation statements)

References 49 publications

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“…The potential role of BACH1 for heme-mediated Spi-C induction in intestinal macrophages was not evaluated in this study. Independently, heme encapsulated in liposomes has been shown to target macrophages at the site of injury after myocardial infarction and to reprogram their inflammatory nature to an anti-inflammatory phenotype [93]. In summary, the administration of heme in vivo has been shown to cause anti-inflammatory polarization of macrophages which might be mediated via BACH-1 degradation and subsequent induction of HO-1 and Spi-C.…”

Section: Heme As An Anti-inflammatory Signal In Macrophagesmentioning

confidence: 99%

Interplay of Heme with Macrophages in Homeostasis and Inflammation

Pradhan

Vijayan

Gueler

et al. 2020

IJMS

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Macrophages are an integral part of the mononuclear phagocyte system that is critical for maintaining immune homeostasis. They play a key role for initiation and modulation of immunological responses in inflammation and infection. Moreover, macrophages exhibit a wide spectrum of tissue-specific phenotypes in steady-state and pathophysiological conditions. Recent clinical and experimental evidence indicates that the ubiquitous compound heme is a crucial regulator of these cells, e.g., in the differentiation of monocytes to tissue-resident macrophages and/ or in activation by inflammatory stimuli. Notably, heme, an iron containing tetrapyrrole, is essential as a prosthetic group of hemoproteins (e.g., hemoglobin and cytochromes), whereas non-protein bound free or labile heme can be harmful via pro-oxidant, pro-inflammatory, and cytotoxic effects. In this review, it will be discussed how the complex interplay of heme with macrophages regulates homeostasis and inflammation via modulating macrophage inflammatory characteristics and/ or hematopoiesis. A particular focus will be the distinct roles of intra- and extracellular labile heme and the regulation of its availability by heme-binding proteins. Finally, it will be addressed how heme modulates macrophage functions via specific transcriptional factors, in particular the nuclear repressor BTB and CNC homologue (BACH)1 and Spi-C.

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Section: Heme As An Anti-inflammatory Signal In Macrophagesmentioning

confidence: 99%

Interplay of Heme with Macrophages in Homeostasis and Inflammation

Pradhan

Vijayan

Gueler

et al. 2020

IJMS

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“…Short-term administration of AOAA led to a decreased proportion of M1 macrophages, an elevated proportion of M2 macrophages, and inactivation of the NLRP3-caspase1/IL-1 beta pathway [81]. In addition, some other agents such as hemin-carried drugs based on lipid [82], NADPH oxidase 4 (Nox4) [83], hyaluronic acid oligosaccharides (o-HA) [84], played possible beneficial roles in restoring cardiac function post MI by targeting cardiac macrophages and skewing them towards an M2 anti-inflammatory phenotype, which provided a novel strategy to regulate inflammation, reduce adverse remodeling, and improve the contractile function of infarcted hearts. Interestingly, some commonly used hypoglycemic drugs had certain effects in ameliorating cardiac remodeling.…”

Section: Potential Therapies Targeting Macrophagesmentioning

confidence: 99%

The Roles of Noncardiomyocytes in Cardiac Remodeling

Yang

Liu

et al. 2020

Int. J. Biol. Sci.

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Cardiac remodeling is a common characteristic of almost all forms of heart disease, including cardiac infarction, valvular diseases, hypertension, arrhythmia, dilated cardiomyopathy and other conditions. It is not merely a simple outcome induced by an increase in the workload of cardiomyocytes (CMs). The remodeling process is accompanied by abnormalities of cardiac structure as well as disturbance of cardiac function, and emerging evidence suggests that a wide range of cells in the heart participate in the initiation and development of cardiac remodeling. Other than CMs, there are numerous noncardiomyocytes (non-CMs) that regulate the process of cardiac remodeling, such as cardiac fibroblasts and immune cells (including macrophages, lymphocytes, neutrophils, and mast cells). In this review, we summarize recent knowledge regarding the definition and significant effects of various non-CMs in the pathogenesis of cardiac remodeling, with a particular emphasis on the involved signaling mechanisms. In addition, we discuss the properties of non-CMs, which serve as targets of many cardiovascular drugs that reduce adverse cardiac remodeling.

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“…Alternative strategies have employed liposomes carrying phosphatidylserine, an “eat me” signal that directs efferocytosis, to increase anti-inflammatory cytokine production by macrophages after myocardial infarction ( 245 ). Other macrophage-targeted lipid based drug carriers are able to reprogram macrophages to a proresolving phenotype and improve tissue repair and limit infarct expansion ( 246 ). With respect to the proteolytic degradation of efferocytic receptors, such as MerTK and CD36 ( 17 , 225 ), strategies which block the cleavage degradation including cleavage-blocking peptides, may be a viable approach for enhancing protection after cardiac insult.…”

Section: Future Prospects For the Therapeutic Targeting Of Phagocyticmentioning

confidence: 99%

Efferocytosis and Outside-In Signaling by Cardiac Phagocytes. Links to Repair, Cellular Programming, and Intercellular Crosstalk in Heart

et al. 2017

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Phagocytic sensing and engulfment of dying cells and extracellular bodies initiate an intracellular signaling cascade within the phagocyte that can polarize cellular function and promote communication with neighboring non-phagocytes. Accumulating evidence links phagocytic signaling in the heart to cardiac development, adult myocardial homeostasis, and the resolution of cardiac inflammation of infectious, ischemic, and aging-associated etiology. Phagocytic clearance in the heart may be carried out by professional phagocytes, such as macrophages, and non-professional cells, including myofibrolasts and potentially epithelial cells. During cardiac development, phagocytosis initiates growth cues for early cardiac morphogenesis. In diseases of aging, including myocardial infarction, heightened levels of cell death require efficient phagocytic debridement to salvage further loss of terminally differentiated adult cardiomyocytes. Additional risk factors, including insulin resistance and other systemic risk factors, contribute to inefficient phagocytosis, altered phagocytic signaling, and delayed cardiac inflammation resolution. Under such conditions, inflammatory presentation of myocardial antigen may lead to autoimmunity and even possible rejection of transplanted heart allografts. Increased understanding of these basic mechanisms offers therapeutic opportunities.

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Targeting and modulating infarct macrophages with hemin formulated in designed lipid-based particles improves cardiac remodeling and function

Cited by 37 publications

References 49 publications

Interplay of Heme with Macrophages in Homeostasis and Inflammation

Interplay of Heme with Macrophages in Homeostasis and Inflammation

The Roles of Noncardiomyocytes in Cardiac Remodeling

Efferocytosis and Outside-In Signaling by Cardiac Phagocytes. Links to Repair, Cellular Programming, and Intercellular Crosstalk in Heart

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