The immune system and cardiac repair

Frangogiannis, Nikolaos G.

doi:10.1016/j.phrs.2008.06.007

Cited by 568 publications

(547 citation statements)

References 347 publications

(342 reference statements)

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“…However, models of myocardial ischemia and/or infarction have illuminated an important, but complicated, function of these inflammatory cells in cardiac injury and repair. For example, monocytes and macrophages are required for the reparative response to myocardial tissue damage, yet overexuberant inflammation and cytokine production can exacerbate pathologic left ventricular (LV) remodeling (8).…”

mentioning

confidence: 99%

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Schilling

Machkovech

Kim

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Schilling JD, Machkovech HM, Kim AH, Schwedwener R, Schaffer JE. Macrophages modulate cardiac function in lipotoxic cardiomyopathy. Am J Physiol Heart Circ Physiol 303: H1366 -H1373, 2012. First published October 5, 2012; doi:10.1152/ajpheart.00111.2012.-Diabetes is associated with myocardial lipid accumulation and an increased risk of heart failure. Although cardiac myocyte lipid overload is thought to contribute to the pathogenesis of cardiomyopathy in the setting of diabetes, the mechanism(s) through which this occurs is not well understood. Increasingly, inflammation has been recognized as a key pathogenic feature of lipid excess and diabetes. In this study, we sought to investigate the role of inflammatory activation in the pathogenesis of lipotoxic cardiomyopathy using the ␣-myosin heavy chain promoter-driven long-chain acylCoA synthetase 1 (MHC-ACS) transgenic mouse model. We found that several inflammatory cytokines were upregulated in the myocardium of MHC-ACS mice before the onset of cardiac dysfunction, and this was accompanied by macrophage infiltration. Depletion of macrophages with liposomal clodrolip reduced the cardiac inflammatory response and improved cardiac function. Thus, in this model of lipotoxic cardiac injury, early induction of inflammation and macrophage recruitment contribute to adverse cardiac remodeling. These findings have implications for our understanding of heart failure in the setting of obesity and diabetes. heart failure; diabetes; inflammation OBESITY AND DIABETES ARE SIGNIFICANT risk factors for the development of heart failure (11). In many diabetic patients, this can occur in the absence of underlying coronary artery disease or hypertension, a phenomenon known as diabetic cardiomyopathy (1). The pathogenesis of diabetic cardiomyopathy is complex; however, myocardial lipid overload is a pathologic feature of this condition in humans and in animal models (6,7,12,25). The observation that cardiac myocyte lipid overload causes cardiomyopathy in genetic mouse models, without systemic abnormalities of insulin or glucose metabolism, supports the notion that excess lipids can be cardiotoxic (4,5,7,32). Membrane lipid remodeling, endoplasmic reticulum and oxidative stress, and production of toxic lipid species, such as ceramides, have been implicated as potential mechanisms of cardiac lipotoxicity (12,23).Systemic inflammation is another hallmark of obesity and diabetes and has been shown to correlate with the risk of heart failure in patients with these metabolic conditions (2). This raises the intriguing possibility that lipid-induced inflammatory responses might contribute to cardiac dysfunction in obesity and diabetes. Much of what is known regarding the link between diabetes and inflammation has come from investigations of adipose tissue. In humans and animals, obesity triggers the recruitment of macrophages to white adipose tissue, which is followed by release of inflammatory mediators and the onset of insulin resistance (26,29). When this response is interrupted in mice fed...

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confidence: 99%

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Schilling

Machkovech

Kim

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…The innate immune system plays a critical role in the initiation and progression of cardiac repair following MI [13][14][15][16]. The post-MI inflammatory response is a well-orchestrated process that is triggered by the injured myocardium and mediated by inflammatory cells including neutrophils and monocytes/macrophages.…”

Section: Damps and The Heartmentioning

confidence: 99%

“…Activation of these receptors is often coupled to inflammatory responses driven by NF B signalling [13,16], although proliferative, migratory and fibrotic outcomes have also been observed in response to different ligands [23][24][25][26].…”

Section: Damp Receptors and Cardiac Remodellingmentioning

confidence: 99%

“…A full description of the role of the innate immune system in cardiac remodelling lies beyond the scope of the present article, but the reader is directed towards several excellent reviews that explore this in more detail [13][14][15][16]. Knockout mouse studies have proven useful for identifying specific roles for DAMP receptors in modulating cardiac remodelling after injury or stress (summarised in Table 1).…”

Section: Damp Receptors and Cardiac Remodellingmentioning

confidence: 99%

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Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

Turner

2016

Journal of Molecular and Cellular Cardiology

166

124

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Cardiac fibroblasts (CF) are well-established as key regulators of extracellular matrix (ECM) turnover in the context of myocardial remodelling and fibrosis. Recently, this cell type has also been shown to act as a sensor of myocardial damage by detecting and responding to damage-associated molecular patterns (DAMPs) upregulated with cardiac injury. CF express a range of innate immunity pattern recognition receptors (TLRs, NLRs, IL-1R1, RAGE) that are stimulated by a host of different DAMPs that are evident in the injured or remodelling myocardium. These include intracellular molecules released by necrotic cells (heat shock proteins, high mobility group box 1 protein, S100 proteins), proinflammatory cytokines (interleukin-1), specific ECM molecules up-regulated in response to tissue injury (fibronectin-EDA, tenascin-C) or molecules modified by a pathological environment (advanced glycation end product-modified proteins observed with diabetes). DAMP receptor activation on fibroblasts is coupled to altered cellular function including changes in proliferation, migration, myofibroblast transdifferentiation, ECM turnover and production of fibrotic and inflammatory paracrine factors, which directly impact on the heart's ability to respond to injury. This review gives an overview of the important role played by CF in responding to myocardial DAMPs and how the DAMP/CF axis could be exploited experimentally and therapeutically.3

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“…This leads to inflammation and scarring with consequent tissue remodelling, as well as mechanical dysfunction and electrical conduction pathway abnormalities (7). MI is listed among the acute coronary syndromes that represent the most common cause of morbidity and mortality in the Western world.…”

Section: Introductionmentioning

confidence: 99%