Macrophages in the Remodeling Failing Heart

Chen, Bijun; Frangogiannis, Nikolaos G.

doi:10.1161/circresaha.116.309624

Cited by 40 publications

(32 citation statements)

References 22 publications

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“…Macrophage facilitates the conduction of electrical impulses in the heart (70). Reduction in the number of macrophages in the heart after infarction in mice has been reported to correlate with increased mortality and impaired cardiac repair (71). Interestingly, TLR2 deficiency is associated with reduced immune cells infiltration in the heart (72).…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Spurthi

Sarikhani

Mishra

et al. 2018

Journal of Biological Chemistry

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Toll-like receptors (TLRs) are a family of patternrecognition receptors involved in innate immunity. Previous studies have shown that TLR2 inhibition protects the heart from acute stress, including myocardial infarction and doxorubicin-induced cardiotoxicity in animal models. However, the role of TLR2 in the development of aging-associated heart failure is not known. In this work, we studied agingassociated changes in structure and function of TLR2-deficient mice hearts. Whereas young TLR2-KO mice did not develop marked cardiac dysfunction, 8-and 12-months-old TLR2-KO mice exhibited spontaneous adverse cardiac remodeling and cardiac dysfunction in an age-dependent manner. The hearts of the 8-monthsold TLR2-KO mice had increased fibrosis, cell death, and reactivation of fetal genes. Moreover, TLR2-KO hearts displayed reduced infiltration by macrophages, increased numbers of myofibroblasts and atrophic cardiomyocytes, and higher levels of the atrophyrelated ubiquitin ligases MuRF-1 and Atrogin-1. Mechanistically, TLR2-deficiency impaired the PI3K/Akt signaling pathway, leading to hyperactivation of the transcription factor forkhead box protein O1 (FoxO1), and, in turn, to elevated expression of FoxO target genes involved in regulation of muscle wasting and cell death. AS1842856-mediated chemical inhibition of FoxO1 reduced the expression of the atrophy-related ubiquitin ligases and significantly reversed the adverse cardiac remodeling, while improving the contractile functions in the TLR2-KO mice. Interestingly, TLR2 levels decreased in hearts of older mice, and activation of TLR1/2 signaling improved cardiac functions in these mice. These findings suggest that TLR2 signaling is essential for protecting the heart against aging-associated adverse remodeling and contractile dysfunction in mice.

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Section: Discussionmentioning

confidence: 99%

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Spurthi

Sarikhani

Mishra

et al. 2018

Journal of Biological Chemistry

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“…It should be emphasized that in the presence of a large infarction with significant hemodynamic consequences, viable noninfarcted myocardium also exhibits slowly progressive interstitial fibrosis related to the pathophysiologic effects of pressure and volume loads. Inflammation and fibrosis are suppressed in the healing infarct, leading to formation of a mature collagen-based scar, but in the viable noninfarcted zone, increased wall stress may locally activate macrophages and fibroblasts, triggering chronic progressive expansion of the cardiac interstitial matrix (97,98).…”

Section: Ecm In the Maturation Phase Of Infarct Healingmentioning

confidence: 99%

The extracellular matrix in myocardial injury, repair, and remodeling

Frangogiannis¹

2017

Journal of Clinical Investigation

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402

318

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“…As such, there has been an increasing interest in the role of Ms in the process of healing and cardiac remodeling after MI. [25][26][27][28] We hypothesized that CDH11 regulates the interactions between CFs and Ms in the heart after MI, noting that M activity has been shown to alter CF function in the ischemic heart independent of CDH11. 29 Interactions between Ms and CFs have been reported to regulate IL-6 expression in response to TGF-β1 signaling and fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Cadherin-11 Blockade Reduces Inflammation-Driven Fibrotic Remodeling and Improves Outcomes After Myocardial Infarction

Schroer

Bersi

Clark

et al. 2019

Preprint

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Background: Over one million Americans experience myocardial infarction (MI) every year, and the resulting scar and subsequent cardiac fibrosis contribute to heart failure and death. A specialized cell-cell adhesion protein, cadherin-11 (CDH11), contributes to inflammation and fibrosis in rheumatoid arthritis, pulmonary fibrosis, and aortic valve calcification but has not yet been studied in the context of cardiac remodeling after MI. We hypothesized that targeting CDH11 function after MI would reduce inflammation-driven fibrotic remodeling and infarct expansion to improve functional outcomes in mice.Methods: MI was induced by ligation of the left anterior descending artery in transgenic mice with reduced or ablated CDH11, wild type mice receiving bone marrow transplants from Cdh11 transgenic animals, and wild type mice treated with a functional blocking antibody against CDH11 (SYN0012). Cardiac function was measured by echocardiography, expression of cell populations was quantified by flow cytometry, and tissue remodeling by altered histological assessment and transcription of inflammatory and pro-angiogenic genes by qPCR. Co-culture was used to assess interactions between cardiac fibroblasts and macrophages.

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Macrophages in the Remodeling Failing Heart

Cited by 40 publications

References 22 publications

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

The extracellular matrix in myocardial injury, repair, and remodeling

Cadherin-11 Blockade Reduces Inflammation-Driven Fibrotic Remodeling and Improves Outcomes After Myocardial Infarction

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