Cardiosphere-Derived Cells Require Endoglin for Paracrine-Mediated Angiogenesis

Redgrave, Rachael; Tual‐Chalot, Simon; Davison, Benjamin; Singh, Ekta; Hall, Darroch; Amirrasouli, M; Gilchrist, Derek S.; Medvinsky, Alexander; Arthur, Helen M.

doi:10.1016/j.stemcr.2017.04.015

Cited by 37 publications

(31 citation statements)

References 42 publications

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“…Finally, we quantified peri-infarct region vascularity. Consistent with an in vivo pro-angiogenic effect, 31 the peri-infarct region 15 of hearts from animals treated with navitoclax had significantly increased vessel density in the peri-infarct zone compared vehicle control (14.38%±2.88% vs 8.87%±1.74 Figure 5F). Taken together our data indicate that in young animals cardiac IR drives senescence and a pro-inflammatory, anti-angiogenic and profibrotic SASP.…”

Section: Navitoclax Treatment Reduces Infarct Size and Promotes Angiosupporting

confidence: 67%

Clearance of senescent cells following cardiac ischemia-reperfusion injury improves recovery

Dookun

Walaszczyk

Redgrave

et al. 2020

Preprint

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Rationale:A key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. We have previously shown that oxidative stress induces myocardial senescence, promoting adverse myocardial remodeling and cardiac dysfunction via the expression of a proinflammatory senescence-associated secretory phenotype (SASP). In this study we hypothesized that oxidative stress-induced senescence and SASP-mediated inflammation contribute to the pathophysiology of cardiac IRI and thus, senescence represents a novel therapeutic target. Objective:To identify if cellular senescence contributes to the pathophysiology of IRI and to investigate if pharmacological elimination of senescent cells after ischemiareperfusion can improve cardiac outcomes. Methods and Results:Using an established model of cardiac ischemia-reperfusion, we demonstrate that in young mice IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations. Additionally, we show that treatment with the senolytic drug navitoclax improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS based proteomics revealed that biological processes associated with fibrosis and inflammation, which were increased following 2 ischemia-reperfusion, were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of proinflammatory, profibrotic and antiangiogenic cytokines, including interferon gamma-induced protein-10, TGF-β3, interleukin-11, interleukin-16 and fractalkine. Conclusions:Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemiareperfusion. We also establish that post-IRI the SASP plays a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemiareperfusion.

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Section: Navitoclax Treatment Reduces Infarct Size and Promotes Angiosupporting

confidence: 67%

Clearance of senescent cells following cardiac ischemia-reperfusion injury improves recovery

Dookun

Walaszczyk

Redgrave

et al. 2020

Preprint

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“…To investigate whether treatment with navitoclax improved outcome following MI, mice from each group were then subjected to ligation of the left anterior descending coronary artery (LAD), which mimics the pathophysiology of MI (Redgrave et al, ).…”

Section: Introduction Results Discussionmentioning

confidence: 99%

Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction

et al. 2019

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Cardiovascular disease is the leading cause of death in individuals over 60 years old. Aging is associated with an increased prevalence of coronary artery disease and a poorer prognosis following acute myocardial infarction (MI). With age, senescent cells accumulate in tissues, including the heart, and contribute to age‐related pathologies. However, the role of senescence in recovery following MI has not been investigated. In this study, we demonstrate that treatment of aged mice with the senolytic drug, navitoclax, eliminates senescent cardiomyocytes and attenuates profibrotic protein expression in aged mice. Importantly, clearance of senescent cells improved myocardial remodelling and diastolic function as well as overall survival following MI. These data provide proof‐of‐concept evidence that senescent cells are major contributors to impaired function and increased mortality following MI and that senolytics are a potential new therapeutic avenue for MI.

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“…Magnetic resonance images were acquired with a horizontal bore 7.0T Varian microimaging system (Varian Inc., Palo Alto, CA, USA) equipped with a 12-cm microimaging gradient insert (40 gauss/cm) and analysed as described previously (Redgrave et al, 2017). Percentage change in wall thickening was calculated from the mean of wall thickness at four points in all slices at end systole and end diastole thickness.…”

Section: Mr Imaging and Analysismentioning

confidence: 99%

Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence

et al. 2019

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Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age‐related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post‐mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age‐related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent‐like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length‐independent telomere damage in cardiomyocytes activates the classical senescence‐inducing pathways, p21CIP and p16INK4a, and results in a non‐canonical senescence‐associated secretory phenotype, which is pro‐fibrotic and pro‐hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age‐related myocardial dysfunction and in the wider setting to ageing in post‐mitotic tissues.

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Cardiosphere-Derived Cells Require Endoglin for Paracrine-Mediated Angiogenesis

Cited by 37 publications

References 42 publications

Clearance of senescent cells following cardiac ischemia-reperfusion injury improves recovery

Clearance of senescent cells following cardiac ischemia-reperfusion injury improves recovery

Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction

Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence

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