A potential role of caspase recruitment domain family member 9 (Card9) in transverse aortic constriction-induced cardiac dysfunction, fibrosis, and hypertrophy

Peterson, Matthew R.; Getiye, Yohannes; Bosch, Luiza; Sanders, Alyssa; Smith, Aspen; Haller, Samantha; Wilson, Kayla; Thomas, D. P.; He, Guanglong

doi:10.1038/s41440-020-0507-0

Cited by 10 publications

(15 citation statements)

References 31 publications

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“…In conclusion, the present study by Peterson et al [9] has provided another solid piece of evidence indicating that CARD9 is likely a key player and not a bystander in cardiac remodeling under hypertension (summarized in Fig. 1).…”

supporting

confidence: 57%

“…Therefore, the observed detrimental effects of CARD9 on the myocardium were likely mediated by its expression in immune cells, particularly macrophages, residing in or infiltrating the myocardium. Another interesting finding of this study is that the fibrotic areas were reduced in CARD9-knockout hearts even under nonstressed control conditions [9], indicating that mild fibrosis may develop with the aging process, and/or resident immune cells expressing CARD9 were present in the myocardium even under nonstressed conditions and that CARD9 may be involved in the maintenance of collagen turnover in healthy hearts.…”

mentioning

confidence: 64%

“…CARD9(−/−) mice exhibited significantly higher numbers of apoptotic cells after myocardial I/R injury than wild-type mice. Conversely, these new discrepant results undoubtedly add more complexity and confusion regarding the opposing protective or detrimental roles of CARD9 in cardiac diseases proposed by various groups [9,12,13].…”

mentioning

confidence: 98%

“…In this context, in the current issue of Hypertension Research, Peterson et al from the University of Wyoming [9] demonstrated a role of CARD9 in pressure overloadinduced pathological cardiac remodeling and dysfunction by means of CARD9-knockout mice subjected to transverse aortic constriction (TAC). This experienced investigative team has focused on CARD9 in various cardiovascular diseases, although the current work is the first report on the role of CARD9 in hypertension-related cardiac remodeling.…”

mentioning

confidence: 99%

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CARD9: key player or bystander in cardiac remodeling under hypertension?

2020

Hypertens Res

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confidence: 57%

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confidence: 64%

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confidence: 98%

mentioning

confidence: 99%

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CARD9: key player or bystander in cardiac remodeling under hypertension?

2020

Hypertens Res

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“…CARD9 plays an essential role in cardiac injury, remodeling (hypertrophy and fibrosis), and dysfunction [12,[43][44][45]. During cardiac dysfunction, the CARD9 signaling-mediated production of inflammatory cytokines (IL-6, IL-1β, TNF-α, and TGF-β) and chemokines (MCP-1/CCL2 and CXCL1), which are mainly secreted by macrophages and neutrophils, in the heart has been investigated.…”

Section: Card9 and Inflammationmentioning

confidence: 99%

CARD9 Regulation and its Role in Cardiovascular Diseases

Zhang¹,

Wang²,

Men³

et al. 2022

Int. J. Biol. Sci.

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Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor protein expressed on myeloid cells and located downstream of pattern recognition receptors (PRRs), which transduces signals involved in innate immunity. CARD9 deficiency is associated with increased susceptibility to various fungal diseases. Increasing evidence shows that CARD9 mediates the activation of p38 MAPK, NF-κB, and NLRP3 inflammasome in various CVDs and then promotes the production of proinflammatory cytokines and chemokines, which contribute to cardiac remodeling and cardiac dysfunction in certain cardiovascular diseases (CVDs). Moreover, CARD9-mediated anti-apoptosis and autophagy are implicated in the progression of CVDs. Here, we summarize the structure and function of CARD9 in innate immunity and its various roles in inflammation, apoptosis, and autophagy in the pathogenesis of CVDs. Furthermore, we discuss the potential therapies targeting CARD9 to prevent CVDs and raise some issues for further exploring the role of CARD9 in CVDs.

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Macrophage OTUD1‐CARD9 axis drives isoproterenol‐induced inflammatory heart remodelling

Qian,

Wang,

et al. 2024

Clinical & Translational Med

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BackgroundChronic inflammation contributes to the progression of isoproterenol (ISO)‐induced heart failure (HF). Caspase‐associated recruitment domain (CARD) families are crucial proteins for initiation of inflammation in innate immunity. Nonetheless, the relevance of CARDs in ISO‐driven cardiac remodelling is little explored.MethodsThis study utilized Card9−/− mice and reconstituted C57BL/6 mice with either Card9−/− or Otud1−/− marrow‐derived cells. Mechanistic studies were conducted in primary macrophages, cardiomyocytes, fibroblasts and HEK‐293T cells.ResultsHere, we demonstrated that CARD9 was substantially upregulated in murine hearts infused with ISO. Either whole‐body CARD9 knockout or myeloid‐specific CARD9 deletion inhibited ISO‐driven murine cardiac inflammation, remodelling and dysfunction. CARD9 deficiency in macrophages prevented ISO‐induced inflammation and alleviated remodelling changes in cardiomyocytes and fibroblasts. Mechanistically, we found that ISO enhances the activity of CARD9 by upregulating ovarian tumour deubiquitinase 1 (OTUD1) in macrophages. We further demonstrated that OTUD1 directly binds to the CARD9 and then removes the K33‐linked ubiquitin from CARD9 to promote the assembly of the CARD9‐BCL10‐MALT1 (CBM) complex, without affecting CARD9 stability. The ISO‐activated CBM complex results in NF‐κB activation and macrophage‐based inflammatory gene overproduction, which then enhances cardiomyocyte hypertrophy and fibroblast fibrosis, respectively. Myeloid‐specific OTUD1 deletion also attenuated ISO‐induced murine cardiac inflammation and remodelling.ConclusionsThese results suggested that the OTUD1‐CARD9 axis is a new pro‐inflammatory signal in ISO‐challenged macrophages and targeting this axis has a protective effect against ISO‐induced HF.Key points Macrophage CARD9 was elevated in heart tissues of mice under chronic ISO administration. Either whole‐body CARD9 knockout or myeloid‐specific CARD9 deficiency protected mice from ISO‐induced inflammatory heart remodeling. ISO promoted the assembly of CBM complex and then activated NF‐κB signaling in macrophages through OTUD1‐mediated deubiquitinating modification. OTUD1 deletion in myeloid cells protected hearts from ISO‐induced injuries in mice.

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A potential role of caspase recruitment domain family member 9 (Card9) in transverse aortic constriction-induced cardiac dysfunction, fibrosis, and hypertrophy

Cited by 10 publications

References 31 publications

CARD9: key player or bystander in cardiac remodeling under hypertension?

CARD9: key player or bystander in cardiac remodeling under hypertension?

CARD9 Regulation and its Role in Cardiovascular Diseases

Macrophage OTUD1‐CARD9 axis drives isoproterenol‐induced inflammatory heart remodelling

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