Macrophages in cardiac remodelling after myocardial infarction.

Myocardial infarction (MI), as a result of thrombosis or vascular occlusion, is the most prevalent cause of morbidity and mortality among all cardiovascular diseases. The devastating consequences of MI are compounded by the complexities of cellular functions involved in the initiation and resolution of early-onset inflammation and the longer-term effects related to scar formation. The resultant tissue damage can occur as early as 1 h after MI and activates inflammatory signalling pathways to elicit an immune response. Macrophages are one of the most active cell types during all stages after MI, including the cardioprotective, inflammatory and tissue repair phases. In this Review, we describe the phenotypes of cardiac macrophage involved in MI and their cardioprotective functions. A specific subset of macrophages called resident cardiac macrophages (RCMs) are derived from yolk sac progenitor cells and are maintained as a self-renewing population, although their numbers decrease with age. We explore sophisticated sequencing techniques that demonstrate the cardioprotective properties of this cardiac macrophage phenotype. Furthermore, we discuss the interactions between cardiac macrophages and other important cell types involved in the pathology and resolution of inflammation after MI. We summarize new and promising therapeutic approaches that target macrophage-mediated inflammation and the cardioprotective properties of RCMs after MI. Finally, we discuss future directions for the study of RCMs in MI and cardiovascular health in general.

Expression of Chitotriosidase in Macrophages Modulates Atherosclerotic Plaque Formation in Hyperlipidemic Mice.

OBJECTIVE: To determine whether overexpression of the chitin degrading enzyme, chitotriosidase (CHIT1), modulates macrophage function and ameliorates atherosclerosis. APPROACH AND RESULTS: Using a mouse model that conditionally overexpresses CHIT1 in macrophages (CHIT1-Tg) crossbred with the Ldlr -/- mouse provided us with a means to investigate the effects of CHIT1 overexpression in the context of atherosclerosis. In vitro, CHIT1 overexpression by murine macrophages enhanced protein expression of IL-4, IL-8, and G-CSF by BMDM upon stimulation with a combination of lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Phosphorylation of ERK1/2 and Akt was also down regulated when exposed to the same inflammatory stimuli. Hyperlipidemic, Ldlr -/--CHIT1-Tg (CHIT1-OE) mice were fed a high-fat diet for 12 weeks in order to study CHIT1 overexpression in atherosclerosis. Although plaque size and lesion area were not affected by CHIT1 overexpression in vivo, the content of hyaluronic acid (HA) and collagen within atherosclerotic plaques of CHIT1-OE mice was significantly greater. Localization of both ECM components was markedly different between groups. CONCLUSIONS: These data demonstrate that CHIT1 alters cytokine expression and signaling pathways of classically activated macrophages. In vivo, CHIT1 modifies ECM distribution and content in atherosclerotic plaques, both of which are important therapeutic targets.

Nanoparticle delivery of cardioprotective therapies.

Acute myocardial infarction (AMI), and the heart failure (HF) that often follows, are leading causes of death and disability worldwide. Crucially, there are currently no effective treatments, other than myocardial reperfusion, for reducing myocardial infarct (MI) size and preventing HF following AMI. Thus, there is an unmet need to discover novel cardioprotective therapies to reduce MI size, and prevent HF in AMI patients. Although a large number of therapies have been shown to reduce MI size in experimental studies, the majority have failed to benefit AMI patients. Failure to deliver cardioprotective therapy to the ischemic heart in sufficient concentrations following AMI is a major factor for the lack of success observed in previous clinical cardioprotection studies. Therefore, new strategies are needed to improve the delivery of cardioprotective therapies to the ischemic heart following AMI. In this regard, nanoparticles have emerged as drug delivery systems for improving the bioavailability, delivery, and release of cardioprotective therapies, and should result in improved efficacy in terms of reducing MI size and preventing HF. In this article, we provide a review of currently available nanoparticles, some of which have been FDA-approved, in terms of their use as drug delivery systems in cardiovascular disease and cardioprotection.

Role of Macrophages in Cardioprotection.

Cardiovascular diseases are the leading cause of mortality worldwide. It is widely known that non-resolving inflammation results in atherosclerotic conditions, which are responsible for a host of downstream pathologies including thrombosis, myocardial infarction (MI), and neurovascular events. Macrophages, as part of the innate immune response, are among the most important cell types in every stage of atherosclerosis. In this review we discuss the principles governing macrophage function in the healthy and infarcted heart. More specifically, how cardiac macrophages participate in myocardial infarction as well as cardiac repair and remodeling. The intricate balance between phenotypically heterogeneous populations of macrophages in the heart have profound and highly orchestrated effects during different phases of myocardial infarction. In the early "inflammatory" stage of MI, resident cardiac macrophages are replaced by classically activated macrophages derived from the bone marrow and spleen. And while the macrophage population shifts towards an alternatively activated phenotype, the inflammatory response subsides giving way to the "reparative/proliferative" phase. Lastly, we describe the therapeutic potential of cardiac macrophages in the context of cell-mediated cardio-protection. Promising results demonstrate innovative concepts; one employing a subset of yolk sac-derived, cardiac macrophages that have complete restorative capacity in the injured myocardium of neonatal mice, and in another example, post-conditioning of cardiac macrophages with cardiosphere-derived cells significantly improved patient's post-MI diagnoses.