Cardiac macrophages prevent sudden death during heart stress

Sugita, Junichi; Fujiu, Katsuhito; Nakayama, Y.; Matsubara, Takumi; Matsuda, Jun; Oshima, Tomokazu; Liu, Yuxiang; Maru, Yujin; Hasumi, Eriko; Kojima, Tadao; Seno, Hiroshi; Asano, Keisuke; Ishijima, Ayumu; Tomii, Naoki; Yamazaki, Masatoshi; Kudo, Fujimi; Sakuma, Ichiro; Nagai, Ryozo; Manabe, Ichiro; Komuro, Issei

doi:10.1038/s41467-021-22178-0

Cited by 47 publications

(58 citation statements)

References 47 publications

(63 reference statements)

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Section: Homeostatic Impact Of Cardiac Macrophagesmentioning

confidence: 99%

“…The development of AV blocks is accelerated by pressure overload, as demonstrated by experiments where cardiac macrophage is depleted using clodronate liposomes, or when the mouse line CX3CR1-DTR and DT administration before pulmonary artery banding resulted in sudden death a few hours after banding, due to the development of a complete AV block and ventricular arrest [ 66 ], which is not observed after the depletion of other immune cells including lymphocytes and granulocytes [ 66 ]. Amphiregulin (Areg) is a membrane protein that could be secreted by multiple cell types, including cardiac-resident macrophages [ 66 ]. In the heart, it was demonstrated that Areg, secreted by cardiac-resident macrophages and acting through the epidermal growth factor receptor (Egfr), promotes the phosphorylation of Cx43 in CMs, resulting in the correct localization of Cx43 in gap junctions between CMs and the enhancement of membrane permeability and cardiac conductivity [ 66 ].…”

Section: Homeostatic Impact Of Cardiac Macrophagesmentioning

confidence: 99%

“…Amphiregulin (Areg) is a membrane protein that could be secreted by multiple cell types, including cardiac-resident macrophages [ 66 ]. In the heart, it was demonstrated that Areg, secreted by cardiac-resident macrophages and acting through the epidermal growth factor receptor (Egfr), promotes the phosphorylation of Cx43 in CMs, resulting in the correct localization of Cx43 in gap junctions between CMs and the enhancement of membrane permeability and cardiac conductivity [ 66 ].…”

Section: Homeostatic Impact Of Cardiac Macrophagesmentioning

confidence: 99%

“…The depletion of cardiac-resident macrophages or genetic depletion or Areg prevented the hypertrophic response, however, this resulted in a great increase in mortality [ 93 ]. Subsequent research by the same group demonstrated that Areg promotes phosphorylation of Cx43 which results in the proper formation of gap junctions among CMs, and enhances cardiac conduction [ 66 ], thus, the depletion of cardiac-resident macrophages or Areg not only blunts the hypertrophic response after pulmonary artery banding but also leads to fatal cardiac arrhythmias development [ 66 , 93 ].…”

Section: Role Of Cardiac Macrophages Following Adult Cardiac Injurymentioning

confidence: 99%

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The Evolving Roles of Cardiac Macrophages in Homeostasis, Regeneration, and Repair

Alvarez‐Argote

O’Meara

2021

IJMS

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Macrophages were first described as phagocytic immune cells responsible for maintaining tissue homeostasis by the removal of pathogens that disturb normal function. Historically, macrophages have been viewed as terminally differentiated monocyte-derived cells that originated through hematopoiesis and infiltrated multiple tissues in the presence of inflammation or during turnover in normal homeostasis. However, improved cell detection and fate-mapping strategies have elucidated the various lineages of tissue-resident macrophages, which can derive from embryonic origins independent of hematopoiesis and monocyte infiltration. The role of resident macrophages in organs such as the skin, liver, and the lungs have been well characterized, revealing functions well beyond a pure phagocytic and immunological role. In the heart, recent research has begun to decipher the functional roles of various tissue-resident macrophage populations through fate mapping and genetic depletion studies. Several of these studies have elucidated the novel and unexpected roles of cardiac-resident macrophages in homeostasis, including maintaining mitochondrial function, facilitating cardiac conduction, coronary development, and lymphangiogenesis, among others. Additionally, following cardiac injury, cardiac-resident macrophages adopt diverse functions such as the clearance of necrotic and apoptotic cells and debris, a reduction in the inflammatory monocyte infiltration, promotion of angiogenesis, amelioration of inflammation, and hypertrophy in the remaining myocardium, overall limiting damage extension. The present review discusses the origin, development, characterization, and function of cardiac macrophages in homeostasis, cardiac regeneration, and after cardiac injury or stress.

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Section: Homeostatic Impact Of Cardiac Macrophagesmentioning

confidence: 99%

Section: Homeostatic Impact Of Cardiac Macrophagesmentioning

confidence: 99%

Section: Homeostatic Impact Of Cardiac Macrophagesmentioning

confidence: 99%

Section: Role Of Cardiac Macrophages Following Adult Cardiac Injurymentioning

confidence: 99%

See 2 more Smart Citations

The Evolving Roles of Cardiac Macrophages in Homeostasis, Regeneration, and Repair

Alvarez‐Argote

O’Meara

2021

IJMS

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“…In a mouse model of right ventricular pressure overload, it was recently shown that cardiac macrophages are involved in the maintenance of cardiac gap junctional communication and impulse conduction by the release of amphiregulin which controls connexin 43 phosphorylation and translocation in cardiomyocytes (Sugita et al, 2021) [114]. The lateralization of gap junctions also occurs in the hearts of Duchenne muscular dystrophy.…”

Section: Gap Junction Remodeling In Cardiomyopathymentioning

confidence: 99%

Remodeling of Cardiac Gap Junctional Cell–Cell Coupling

Dhein

Salameh

2021

Cells

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The heart works as a functional syncytium, which is realized via cell-cell coupling maintained by gap junction channels. These channels connect two adjacent cells, so that action potentials can be transferred. Each cell contributes a hexameric hemichannel (=connexon), formed by protein subuntis named connexins. These hemichannels dock to each other and form the gap junction channel. This channel works as a low ohmic resistor also allowing the passage of small molecules up to 1000 Dalton. Connexins are a protein family comprising of 21 isoforms in humans. In the heart, the main isoforms are Cx43 (the 43 kDa connexin; ubiquitous), Cx40 (mostly in atrium and specific conduction system), and Cx45 (in early developmental states, in the conduction system, and between fibroblasts and cardiomyocytes). These gap junction channels are mainly located at the polar region of the cardiomyocytes and thus contribute to the anisotropic pattern of cardiac electrical conductivity. While in the beginning the cell–cell coupling was considered to be static, similar to an anatomically defined structure, we have learned in the past decades that gap junctions are also subject to cardiac remodeling processes in cardiac disease such as atrial fibrillation, myocardial infarction, or cardiomyopathy. The underlying remodeling processes include the modulation of connexin expression by e.g., angiotensin, endothelin, or catecholamines, as well as the modulation of the localization of the gap junctions e.g., by the direction and strength of local mechanical forces. A reduction in connexin expression can result in a reduced conduction velocity. The alteration of gap junction localization has been shown to result in altered pathways of conduction and altered anisotropy. In particular, it can produce or contribute to non-uniformity of anisotropy, and thereby can pre-form an arrhythmogenic substrate. Interestingly, these remodeling processes seem to be susceptible to certain pharmacological treatment.

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Advancing Engineered Heart Muscle Tissue Complexity with Hydrogel Composites

Dickerson

2022

Advanced Biology

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A heart attack results in the permanent loss of heart muscle and can lead to heart disease, which kills more than 7 million people worldwide each year. To date, outside of heart transplantation, current clinical treatments cannot regenerate lost heart muscle or restore full function to the damaged heart. There is a critical need to create engineered heart tissues with structural complexity and functional capacity needed to replace damaged heart muscle. The inextricable link between structure and function suggests that hydrogel composites hold tremendous promise as a biomaterial‐guided strategy to advance heart muscle tissue engineering. Such composites provide biophysical cues and functionality as a provisional extracellular matrix that hydrogels cannot on their own. This review describes the latest advances in the characterization of these biomaterial systems and using them for heart muscle tissue engineering. The review integrates results across the field to provide new insights on critical features within hydrogel composites and perspectives on the next steps to harnessing these promising biomaterials to faithfully reproduce the complex structure and function of native heart muscle.

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Cardiac macrophages prevent sudden death during heart stress

Cited by 47 publications

References 47 publications

The Evolving Roles of Cardiac Macrophages in Homeostasis, Regeneration, and Repair

The Evolving Roles of Cardiac Macrophages in Homeostasis, Regeneration, and Repair

Remodeling of Cardiac Gap Junctional Cell–Cell Coupling

Advancing Engineered Heart Muscle Tissue Complexity with Hydrogel Composites

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