Dimethyl fumarate preserves left ventricular infarct integrity following myocardial infarction via modulation of cardiac macrophage and fibroblast oxidative metabolism

Mouton, Alan J.; Flynn, Elizabeth R.; Moak, Sydney P.; Aitken, Nikaela; Omoto, Ana Carolina Mieko; Li, Xuan; Silva, Alexandre A. da; Wang, Zhen; Carmo, Jussara M. do; Hall, John E.

doi:10.1016/j.yjmcc.2021.05.008

Cited by 25 publications

(15 citation statements)

References 44 publications

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“…Cardiac wound healing is characterized by different steps involving the generation of new vessels, fibroblast proliferation and differentiation, the deposition of extracellular matrix (ECM), and reepithelialization. Macrophages have been shown to play a pivotal role in orchestrating tissue repair including activation of fibroblasts ( 27 , 28 ). Such an ability is significantly compromised in mitochondria-deficient macrophages, as shown here, partly due to defective efferocytosis and, consequently, reduced expression of prohealing cytokines and tissue growth factors, such as TGF-β.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction

Cai¹,

Zhao²,

Zhou³

et al. 2023

Journal of Clinical Investigation

107

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Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found myeloid specific deletion of mitochondrial Complex I protein Ndufs4 (mKO) reproduced the pro-inflammatory metabolic profile in macrophages and exaggerated the response to lipopolysacharride. Moreover, mKO mice showed increased mortality, poor scar formation and worsened cardiac function 30 days post-MI. We observed a greater inflammatory response in mKO on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to reparative phase during day 3-7 post-MI. Efferocytosis is impaired in mKO macrophages leading to lower expression of anti-inflammatory cytokine and tissue repair factors, which suppressed the proliferation/activation of myofibroblasts in the infarct area. Mitochondria-targeted ROS scavenging rescued these impairments and improved myofibroblast function in vivo and reduced post-MI mortality in mKO mice. Together these results reveal a critical role of mitochondria in inflammation resolution and tissue repair via modulating efferocytosis and crosstalk with fibroblasts. The findings are significant for post-MI recovery as well as for other inflammatory conditions.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction

Cai¹,

Zhao²,

Zhou³

et al. 2023

Journal of Clinical Investigation

107

View full text Add to dashboard Cite

show abstract

“…Urolithin A, a type of gut bacterial metabolite, inhibits myocardial fibrosis by activating the Nrf2 pathway ( Chen et al, 2022d ). Additionally, dimethyl fumarate promotes anti-inflammatory and preparative regulation by modulating oxidative metabolism in macrophages and CFs ( Mouton et al, 2021 ). Furthermore, atypical chemokine receptor four deletion inhibits IL-6 expression and CFs proliferation to alleviate cardiac remodeling ( Zhang et al, 2021a ; Zhang et al, 2021b ).…”

Section: Interventions For Cardiac Fibrosismentioning

confidence: 99%

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

Yin

Pan

et al. 2023

Front. Pharmacol.

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Cardiac fibrosis plays an indispensable role in cardiac tissue homeostasis and repair after myocardial infarction (MI). The cardiac fibroblast-to-myofibroblast differentiation and extracellular matrix collagen deposition are the hallmarks of cardiac fibrosis, which are modulated by multiple signaling pathways and various types of cells in time-dependent manners. Our understanding of the development of cardiac fibrosis after MI has evolved in basic and clinical researches, and the regulation of fibrotic remodeling may facilitate novel diagnostic and therapeutic strategies, and finally improve outcomes. Here, we aim to elaborate pathophysiology, examination and intervention of cardiac fibrosis after MI.

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“…Conversely, a knockdown of HIF-1α in bone marrow cells antagonizes the deterioration of cardiac function after AMI ( 76 ). The compound dimethyl fumarate (DMF) significantly improves cardiac function post-AMI, which leads to a decrease in the expression of HIF-1α and IL-1β, but is also accompanied by an increase in macrophage oxidative phosphorylation levels ( 77 ). The above studies suggest that macrophage metabolic reprogramming is one of the mechanisms regulating macrophage phenotype and function.…”

Section: Transcriptional Regulation Of Macrophage Phenotype and Funct...mentioning

confidence: 99%

Transcriptional regulation of macrophages in heart failure

Wang

Sun

et al. 2023

Front. Cardiovasc. Med.

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Adverse cardiac remodeling after acute myocardial infarction is the most important pathological mechanism of heart failure and remains a major problem in clinical practice. Cardiac macrophages, derived from tissue resident macrophages and circulating monocyte, undergo significant phenotypic and functional changes following cardiac injury and play crucial roles in inflammatory response and tissue repair response. Currently, numerous studies indicate that epigenetic regulatory factors and transcription factors can regulate the transcription of inflammatory and reparative genes and timely conversion of inflammatory macrophages into reparative macrophages and then alleviate cardiac remodeling. Accordingly, targeting transcriptional regulation of macrophages may be a promising option for heart failure treatment. In this review, we not only summarize the origin and function of cardiac macrophages, but more importantly, describe the transcriptional regulation of macrophages in heart failure, aiming to provide a potential therapeutic target for heart failure.

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Dimethyl fumarate preserves left ventricular infarct integrity following myocardial infarction via modulation of cardiac macrophage and fibroblast oxidative metabolism

Cited by 25 publications

References 44 publications

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

Transcriptional regulation of macrophages in heart failure

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