Essential Role for Premature Senescence of Myofibroblasts in Myocardial Fibrosis

Meyer, Kathleen; Hodwin, Bettina; Ramanujam, Deepak; Engelhardt, Stefan; Sarikas, Antonio

doi:10.1016/j.jacc.2016.02.047

Cited by 210 publications

(182 citation statements)

References 41 publications

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“…In the heart, ischemia/reperfusion induces CCN1 expression in cardiomyocytes, serving as an autocrine function to mediate the cardioprotective effects 15. Another study demonstrated that cardiac‐specific overexpression of CCN1 possessed antifibrosis effects in cardiac fibrosis, suggesting that CCN1 linked a cardiomyocyte–fibroblast interaction 10. Considering that pathological fibrosis is vital in AMI‐induced heart malfunction, we speculate that cardiomyocyte‐derived CCN1 may protect the heart by preventing pathological fibrosis.…”

Section: Introductionmentioning

confidence: 86%

“…It was reported that myofibroblast senescence possessed antifibrosis effects in cardiac fibrosis 10. Moreover, cardiomyocyte senescence is implicated in the myocardial damage caused by doxorubicin and obesity 16, 17.…”

Section: Introductionmentioning

confidence: 99%

“…Stress‐induced senescence or age‐independent premature senescence is used to describe the phenomenon in which various stressors, such as oncogenic events and ionizing radiation, instigate cellular dysfunction 6, 7. Additionally, it is becoming evident that senescence also exerts beneficial roles in normal embryonic development and tissue repair processes 8, 9, 10. Mechanically, senescent cells can affect surrounding cells and play active roles in tissue remodeling by secreting such proteins as proinflammatory cytokines, chemokines, and growth factors (senescence‐associated secretory phenotype, SASP) 11.…”

Section: Introductionmentioning

confidence: 99%

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Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA4‐Dependent CCN1 Secretion

Cui

Xue

Yang

et al. 2018

JAHA

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BackgroundStress‐induced cell premature senescence participates in a variety of tissue and organ remodeling by secreting such proteins as proinflammatory cytokines, chemokines, and growth factors. However, the role of cardiomyocyte senescence in heart remodeling after acute myocardial infarction has not been thoroughly elucidated to date. Therefore, we sought to clarify the impact of premature myocardial senescence on postinfarction heart function.Methods and ResultsSenescence markers, including p16INK 4a, p21CIP 1/ WAF 1, and SA‐β‐gal staining, were analyzed in several heart disease models by immunostaining. Both postinfarction mouse hearts and ischemic human myocardium demonstrated increased senescence markers. Additionally, senescence‐related secretory phenotype was activated after acute myocardial infarction, which upregulated senescence‐related secretory phenotype factors, including CCN family member 1 (CCN1), interleukin‐1α, tumor necrosis factor α, and monocyte chemoattractant protein‐1. In vivo, a tail vein injection of AAV9‐Gata4‐shRNA significantly attenuated senescence‐related secretory phenotype secretion and aggravated postinfarction heart dysfunction. Furthermore, among activated senescence‐related secretory phenotype factors, CCN1 administration reduced myofibroblast viability in vitro and rescued the deleterious effect of AAV9‐Gata4‐shRNA in vivo.ConclusionsMyocardial premature senescence was observed in the ischemic hearts and improved postinfarction heart function, partly through the GATA‐binding factor 4‐CCN1 pathway.

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Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA4‐Dependent CCN1 Secretion

Cui

Xue

Yang

et al. 2018

JAHA

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“…Genetic inactivation of senescence effectors accelerates the development and complexity of atherosclerotic plaques (Merched and Chan, 2004; Guevara et al, 1999) and increases fibrosis following transverse aortic constriction (Meyer et al, 2016). These findings mirror conclusions derived from studies of senescence effector inactivation in liver, which support restrictive function in fibrotic pathogenesis (Krizhanovsky et al, 2008).…”

Section: Cellular Senescence: Aging Mechanism Activated By Nutrienmentioning

confidence: 99%

“…Comparable phenomena have been observed in cardiac tissue, wherein, accumulation of senescence markers is associated with vascular endothelial and cardiac impairments, and clearance of senescent cells improves cardiovascular dysfunction (Roos et al, 2016). Antithetically, defective senescence effector function intensifies cardiovascular disease (Merched and Chan, 2004; Guevara et al, 1999; Meyer et al, 2016). Since p16 INK4a , p53, and p21 exert well-known pleiotropic functions, which convey both anti-proliferative and pro-aging effects, context is essential for interpreting results.…”

Section: Conclusion and Future Studiesmentioning

confidence: 99%

Cellular senescence: Implications for metabolic disease

Schafer

Miller

LeBrasseur

2017

Molecular and Cellular Endocrinology

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The growing burden of obesity- and aging-related diseases has hastened the search for governing biological processes. Cellular senescence is a stress-induced state of stable growth arrest strongly associated with aging that is aberrantly activated by obesity. The transition of a cell to a senescent state is demarcated by an array of phenotypic markers, and leveraging their context-dependent presentation is essential for determining the influence of senescent cells on tissue pathogenesis. Biomarkers of senescent cells have been identified in tissues that contribute to metabolic disease, including fat, liver, skeletal muscle, pancreata, and cardiovascular tissue, suggesting that pharmacological and behavioral interventions that alter their abundance and/or behavior may be a novel therapeutic strategy. However, contradictory findings with regard to a protective versus deleterious role of senescent cells in certain contexts emphasize the need for additional studies to uncover the complex interplay that defines multi-organ disease processes associated with obesity and aging.

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Fibroblast‐mediated intercellular crosstalk in the healthy and diseased heart

et al. 2021

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Cardiac fibroblasts constitute a major cell population in the heart. They secrete extracellular matrix components and various other factors shaping the microenvironment of the heart. In silico analysis of intercellular communication based on single‐cell RNA sequencing revealed that fibroblasts are the source of the majority of outgoing signals to other cell types. This observation suggests that fibroblasts play key roles in orchestrating cellular interactions that maintain organ homeostasis but that can also contribute to disease states. Here, we will review the current knowledge of fibroblast interactions in the healthy, diseased, and aging heart. We focus on the interactions that fibroblasts establish with other cells of the heart, specifically cardiomyocytes, endothelial cells and immune cells, and particularly those relying on paracrine, electrical, and exosomal communication modes.

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Essential Role for Premature Senescence of Myofibroblasts in Myocardial Fibrosis

Abstract: Our data establish premature senescence of myofibroblasts as an essential antifibrotic mechanism and potential therapeutic target in myocardial fibrosis.

Cited by 210 publications

References 41 publications

Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA4‐Dependent CCN1 Secretion

Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA4‐Dependent CCN1 Secretion

Cellular senescence: Implications for metabolic disease

Fibroblast‐mediated intercellular crosstalk in the healthy and diseased heart

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