The role of semaphorins in cardiovascular diseases: Potential therapeutic targets and novel biomarkers

Yin, Zheng; Zhang, Jishou; Xu, Shou-Xi; Liu, Jianfang; Xu, Yao; Yu, Jin; Zhao, Mengmeng; Pan, Wei; Wang, Menglong; Wan, Jun

doi:10.1096/fj.202200844r

Cited by 7 publications

(6 citation statements)

References 124 publications

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“…The receptor complex (NRP1+PLXNA2) associated with SEMA3B was found to be expressed in macrophages and vascular endothelial cells. Despite extensive research on various semaphorin family proteins in cardiovascular diseases, 43 the potential impact of enhanced SEMA3B signaling broadcast by adipocytes on the development of atherosclerosis remains unexplored. Together, our analysis revealed alterations in intercellular communication within pericoronary EAT from patients with CAD.…”

Section: Resultsmentioning

confidence: 99%

Single-Nucleus Transcriptomic Atlas of Human Pericoronary Epicardial Adipose Tissue in Normal and Pathological Conditions

Liu,

Yuan,

Zhao

et al. 2024

ATVB

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BACKGROUND: Pericoronary epicardial adipose tissue (EAT) is a unique visceral fat depot that surrounds the adventitia of the coronary arteries without any anatomic barrier. Clinical studies have demonstrated the association between EAT volume and increased risks for coronary artery disease (CAD). However, the cellular and molecular mechanisms underlying the association remain elusive. METHODS: We performed single-nucleus RNA sequencing on pericoronary EAT samples collected from 3 groups of subjects: patients undergoing coronary bypass surgery for severe CAD (n=8), patients with CAD with concomitant type 2 diabetes (n=8), and patients with valvular diseases but without concomitant CAD and type 2 diabetes as the control group (n=8). Comparative analyses were performed among groups, including cellular compositional analysis, cell type–resolved transcriptomic changes, gene coexpression network analysis, and intercellular communication analysis. Immunofluorescence staining was performed to confirm the presence of CAD-associated subclusters. RESULTS: Unsupervised clustering of 73 386 nuclei identified 15 clusters, encompassing all known cell types in the adipose tissue. Distinct subpopulations were identified within primary cell types, including adipocytes, adipose stem and progenitor cells, and macrophages. CD83 high macrophages and FOSB high adipocytes were significantly expanded in CAD. In comparison to normal controls, both disease groups exhibited dysregulated pathways and altered secretome in the primary cell types. Nevertheless, minimal differences were noted between the disease groups in terms of cellular composition and transcriptome. In addition, our data highlight a potential interplay between dysregulated circadian clock and altered physiological functions in adipocytes of pericoronary EAT. ANXA1 and SEMA3B were identified as important adipokines potentially involved in functional changes of pericoronary EAT and CAD pathogenesis. CONCLUSIONS: We built a complete single-nucleus transcriptomic atlas of human pericoronary EAT in normal and diseased conditions of CAD. Our study lays the foundation for developing novel therapeutic strategies for treating CAD by targeting and modifying pericoronary EAT functions.

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Section: Resultsmentioning

confidence: 99%

Single-Nucleus Transcriptomic Atlas of Human Pericoronary Epicardial Adipose Tissue in Normal and Pathological Conditions

Liu,

Yuan,

Zhao

et al. 2024

ATVB

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“…Semaphorins, plexins, and neuropilins expressed on immune cells regulate various immune responses including migration, proliferation, differentiation, and activation [ 3 ]. Altered semaphorin signaling is implicated in the pathogenesis of chronic inflammatory disorders, including autoimmune diseases [ 51 ], cancer [ 52 ], immunometabolic diseases [ 53 ], and cardiovascular diseases [ 54 ]. These studies highlight the diverse role of semaphorins in the neural and immune systems both in physiological and pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

“…Altered sympathetic innervation is observed in patients with atrial fibrillation and heart failure [ 62 ]. Semaphorin signaling contributes to heart development mainly in vascular patterning and cardiac morphogenesis [ 63 ], and dysregulation of semaphorin signaling has been implicated in several cardiovascular diseases [ 54 ].…”

Section: Introductionmentioning

confidence: 99%

Pathophysiological functions of semaphorins in the sympathetic nervous system

2023

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Upon exposure to external stressors, the body senses them and activates the sympathetic nervous system (SNS) to maintain the homeostasis, which is known as the “fight-or-flight” response. Recent studies have revealed that the SNS also plays pivotal roles in regulating immune responses, such as hematopoiesis, leukocyte mobilization, and inflammation. Indeed, overactivation of the SNS causes many inflammatory diseases, including cardiovascular diseases, metabolic disorders, and autoimmune diseases. However, the molecular basis essential for SNS-mediated immune regulation is not completely understood. In this review, we focus on axon guidance cues, semaphorins, which play multifaceted roles in neural and immune systems. We summarize the functions of semaphorins in the crosstalk between the SNS and the immune system, exploring its pathophysiological roles.

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“…Semaphorins were initially discovered as axonal guidance molecules in the development of the nervous system [7]. Subsequent research revealed their involvement in a variety of other physiological and pathophysiological processes, such as vascular growth [8], gene expression reprogramming of cancer cells [9], tumor progression [7], allergic diseases [10], cardiovascular diseases [11], metabolic disorders [12] or liver diseases [13,14]. Recently, increased focus has been placed on "immune semaphorins" and their roles in regulating immune cell activation, differentiation, mobility and migration in autoimmune diseases [15].…”

Section: Introductionmentioning

confidence: 99%

Association of Immune Semaphorins with COVID-19 Severity and Outcomes

Vargovic,

Papic,

Samadan

et al. 2023

Biomedicines

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Semaphorins have recently been recognized as crucial modulators of immune responses. In the pathogenesis of COVID-19, the activation of immune responses is the key factor in the development of severe disease. This study aimed to determine the association of serum semaphorin concentrations with COVID-19 severity and outcomes. Serum semaphorin concentrations (SEMA3A, -3C, -3F, -4D, -7A) were measured in 80 hospitalized adult patients with COVID-19 (moderate (n = 24), severe (n = 32), critical, (n = 24)) and 40 healthy controls. While SEMA3C, SEMA3F and SEMA7A serum concentrations were significantly higher in patients with COVID-19, SEMA3A was significantly lower. Furthermore, SEMA3A and SEMA3C decreased with COVID-19 severity, while SEMA3F and SEMA7A increased. SEMA4D showed no correlation with disease severity. Serum semaphorin levels show better predictive values than CRP, IL-6 and LDH for differentiating critical from moderate/severe COVID-19. SEMA3F and SEMA7A serum concentrations were associated with the time to recovery, requirement of invasive mechanical ventilation, development of pulmonary thrombosis and nosocomial infections, as well as with in-hospital mortality. In conclusion, we provide the first evidence that SEMA3A, SEMA3C, SEMA3F and SEMA7A can be considered as new biomarkers of COVID-19 severity.

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The role of semaphorins in cardiovascular diseases: Potential therapeutic targets and novel biomarkers

Cited by 7 publications

References 124 publications

Single-Nucleus Transcriptomic Atlas of Human Pericoronary Epicardial Adipose Tissue in Normal and Pathological Conditions

Single-Nucleus Transcriptomic Atlas of Human Pericoronary Epicardial Adipose Tissue in Normal and Pathological Conditions

Pathophysiological functions of semaphorins in the sympathetic nervous system

Association of Immune Semaphorins with COVID-19 Severity and Outcomes

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