The Fire Within: Cardiac Inflammatory Signaling in Health and Disease

Coggins, Matthew; Rosenzweig, Anthony

doi:10.1161/circresaha.111.243196

Cited by 81 publications

(74 citation statements)

References 95 publications

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“…Inflammatory processes are involved in many conditions that injure the myocardium and cause both structural and functional defects in the heart (15,16), and glucocorticoids have welldocumented anti-inflammatory actions. Examination of the genes dysregulated in the hearts of the cardioGRKO mice by both IPA and GO revealed a prominent association with the immune response and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

Oakley

Ren²,

Cruz‐Topete³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

115

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Significance Stress is increasingly associated with heart disease. Glucocorticoids are primary stress hormones, yet their direct role in the heart is poorly understood. Mice lacking the glucocorticoid receptor specifically in cardiomyocytes die prematurely from heart failure. The deficiency in glucocorticoid signaling leads to the aberrant regulation of a large cohort of genes strongly associated with both cardiovascular and inflammatory disease processes. These findings reveal an obligate role for cardiomyocyte glucocorticoid receptors in maintaining normal heart function and define a paradigm for stress in cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

Oakley

Ren²,

Cruz‐Topete³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

115

View full text Add to dashboard Cite

show abstract

“…While the initial effects may be protective, a dysregulated and persistent inflammatory reaction becomes pathological and contributes to accentuating cardiac damage and dysfunction. 44 The nature of the immune response depends on the initial trigger, and will therefore vary among etiologies of heart failure. 42,45 The mechanisms that orchestrate these responses within the heart are still being uncovered, but it is increasingly evident that the innate immune system plays an important role in initiating, integrating and perpetuating the cardiac stress responses during heart failure.…”

Section: Immune Activation In Cardiac Diseasementioning

confidence: 99%

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

et al. 2013

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Sustained pressure overload induces heart failure, the main cause of mortality in the Western world. Increased understanding of the underlying molecular mechanisms is essential to improve heart failure treatment. Despite important functions in other tissues, cardiac proteoglycans have received little attention. Syndecan‐4, a transmembrane heparan sulfate proteoglycan, is essential for pathological remodeling, and we here investigated its expression and shedding during heart failure. Pressure overload induced by aortic banding for 24 h and 1 week in mice increased syndecan‐4 mRNA, which correlated with mRNA of inflammatory cytokines. In cardiac myocytes and fibroblasts, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide through the toll‐like receptor‐4, induced syndecan‐4 mRNA. Bioinformatical and mutational analyses in HEK293 cells identified a functional site for the proinflammatory nuclear factor‐κB transcription factor in the syndecan‐4 promoter, and nuclear factor‐κB regulated syndecan‐4 mRNA in cardiac cells. Interestingly, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide induced nuclear factor‐κB‐dependent shedding of the syndecan‐4 ectodomain from cardiac cells. Overexpression of syndecan‐4 with mutated enzyme‐interacting domains suggested enzyme‐dependent heparan sulfate chains to regulate shedding. In cardiac fibroblasts, lipopolysaccharide reduced focal adhesion assembly, shown by immunohistochemistry, suggesting that inflammation‐induced shedding affects function. After aortic banding, a time‐dependent cardiac recruitment of T lymphocytes was observed by measuring CD3, CD4 and CD8 mRNA, which was reduced in syndecan‐4 knockout hearts. Finally, syndecan‐4 mRNA and shedding were upregulated in failing human hearts. Conclusively, our data suggest that syndecan‐4 plays an important role in the immune response of the heart to increased pressure, influencing cardiac remodeling and failure progression.

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“…Inflammation can impede recovery of the adult heart from injury (18). Recent studies demonstrated that disruption of C/ EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function (19).…”

Section: Introductionmentioning

confidence: 99%

Macrophages are required for neonatal heart regeneration

Aurora¹,

et al. 2014

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Myocardial infarction (MI) leads to cardiomyocyte death, which triggers an immune response that clears debris and restores tissue integrity. In the adult heart, the immune system facilitates scar formation, which repairs the damaged myocardium but compromises cardiac function. In neonatal mice, the heart can regenerate fully without scarring following MI; however, this regenerative capacity is lost by P7. The signals that govern neonatal heart regeneration are unknown. By comparing the immune response to MI in mice at P1 and P14, we identified differences in the magnitude and kinetics of monocyte and macrophage responses to injury. Using a cell-depletion model, we determined that heart regeneration and neoangiogenesis following MI depends on neonatal macrophages. Neonates depleted of macrophages were unable to regenerate myocardia and formed fibrotic scars, resulting in reduced cardiac function and angiogenesis. Immunophenotyping and gene expression profiling of cardiac macrophages from regenerating and nonregenerating hearts indicated that regenerative macrophages have a unique polarization phenotype and secrete numerous soluble factors that may facilitate the formation of new myocardium. Our findings suggest that macrophages provide necessary signals to drive angiogenesis and regeneration of the neonatal mouse heart. Modulating inflammation may provide a key therapeutic strategy to support heart regeneration.

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The Fire Within: Cardiac Inflammatory Signaling in Health and Disease

Cited by 81 publications

References 95 publications

Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

Macrophages are required for neonatal heart regeneration

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