Senescence and senolytics in cardiovascular disease: Promise and potential pitfalls

Owens, W. Andrew; Walaszczyk, Anna; Spyridopoulos, Ioakim; Dookun, Emily; Richardson, Gavin D.

doi:10.1016/j.mad.2021.111540

Cited by 68 publications

(73 citation statements)

References 181 publications

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“…However, these complications and alterations are potentially rare, especially with prolonged use, daily treatment and high doses as in the treatment of chronic myelogenous leukemia. They include prolongation of the QT interval, arrhythmia and palpitations [ 56 ]. On the other hand, low-dose Dasatinib was found to ameliorate hypertrophic cardiomyopathy progression [ 57 ] so that the use of Dasatinib in low dose and short time is relatively safe.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Autophagic Flux, Suppressed Apoptosis and Reduced Macrophage Infiltration by Dasatinib in Kidneys of Obese Mice

Elsayed

El-Gamal

Rabei

et al. 2022

Cells

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Obesity causes renal changes (ORC), characterized by defective renal autophagy, lipogenesis, enhanced macrophage infiltration and apoptosis. We hypothesize that Dasatinib, a tyrosine kinase inhibitor, may ameliorate changes associated with obesity. We the mice with either Obesogenic diet (OD) or a standard basal diet. After 12 weeks, the mice received either vehicle or Dasatinib 4 mg/kg/d for an additional four weeks. We examined serum creatinine, urea, lipid profile and renal cortical mRNA expression for lipogenesis marker SREBP1, inflammatory macrophage marker iNOS and fibrosis markers; TGFβ and PDGFA genes; immunohistochemical (IHC) staining for CD68; inflammatory macrophage marker and ASMA; fibrosis marker, LC3 and SQSTM1/P62; autophagy markers and western blotting (WB) for caspase-3; and, as an apoptosis marker, LC3II/I and SQSTM1/P62 in addition to staining for H&E, PAS, Sirius red and histopathological scoring. Dasatinib attenuated renal cortical mRNA expression for SREBP1, iNOS, PDGFA and TGFβ and IHC staining for CD68, ASMA and SQSTM1/P62 and WB for caspase-3 and SQSTM1/P62, while elevating LC3 expression. Moreover, Dasatinib ameliorated ORC; glomerulosclerosis, glomerular expansion, tubular dilatation, vacuolation and casts; inflammatory cellular infiltration; and fibrosis. Dasatinib is a promising therapy for ORC by correcting autophagy impairment, attenuating lipogenesis, apoptosis and macrophage infiltration by inducing antifibrotic activity.

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Section: Discussionmentioning

confidence: 99%

Enhanced Autophagic Flux, Suppressed Apoptosis and Reduced Macrophage Infiltration by Dasatinib in Kidneys of Obese Mice

Elsayed

El-Gamal

Rabei

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…However due to variations in patient responsiveness to treatment owing to the multifactorial nature of atherosclerosis, which results in weak regenerative potential, continuous efforts are needed to provide anti-atherogenic agents with varied mechanisms of action. Targeting SC populations appeared as a valuable strategy since many studies have demonstrated that senescence contributes to the pathophysiology of several age-related including CVDs [ 233 , 234 ]. It was recently reported that senolysis reverses aging phenotype in cardiovascular disorders.…”

Section: Established and Emerging Therapeutical Strategies For Atherosclerosismentioning

confidence: 99%

“…It was recently reported that senolysis reverses aging phenotype in cardiovascular disorders. Generating therapies targeting elimination of SCs or senoprotective pathways would inhibit the progression of undesirable features of aging, and become promising therapies for CVDs [ 234 ].…”

Section: Established and Emerging Therapeutical Strategies For Atherosclerosismentioning

confidence: 99%

Inflammation, Oxidative Stress, Senescence in Atherosclerosis: Thioredoxine-1 as an Emerging Therapeutic Target

Hadri

Smith

Duplus

et al. 2021

IJMS

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Atherosclerosis is a leading cause of cardiovascular diseases (CVD) worldwide and intimately linked to aging. This pathology is characterized by chronic inflammation, oxidative stress, gradual accumulation of low-density lipoproteins (LDL) particles and fibrous elements in focal areas of large and medium arteries. These fibrofatty lesions in the artery wall become progressively unstable and thrombogenic leading to heart attack, stroke or other severe heart ischemic syndromes. Elevated blood levels of LDL are major triggering events for atherosclerosis. A cascade of molecular and cellular events results in the atherosclerotic plaque formation, evolution, and rupture. Moreover, the senescence of multiple cell types present in the vasculature were reported to contribute to atherosclerotic plaque progression and destabilization. Classical therapeutic interventions consist of lipid-lowering drugs, anti-inflammatory and life style dispositions. Moreover, targeting oxidative stress by developing innovative antioxidant agents or boosting antioxidant systems is also a well-established strategy. Accumulation of senescent cells (SC) is also another important feature of atherosclerosis and was detected in various models. Hence, targeting SCs appears as an emerging therapeutic option, since senolytic agents favorably disturb atherosclerotic plaques. In this review, we propose a survey of the impact of inflammation, oxidative stress, and senescence in atherosclerosis; and the emerging therapeutic options, including thioredoxin-based approaches such as anti-oxidant, anti-inflammatory, and anti-atherogenic strategy with promising potential of senomodulation.

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“…Recently, a new approach has been developed using nanocapsules whose cargo are senolytic drugs (specific and unspecific) in mice to deliver to the senescent cells [ 157 ]. In this regard, senotherapy was used to treat senescent cells’ accumulation in CVD, preventing disease evolution [ 160 ]. In this sense, preclinical studies have focused on preventing or reversing a wide range of aging and premature aging diseases, CVD associated-CKD, using senolytic drugs [ 160 ].…”

Section: Unraveling Underlying Mechanisms: Therapeutical Approachesmentioning

confidence: 99%

“…In this regard, senotherapy was used to treat senescent cells’ accumulation in CVD, preventing disease evolution [ 160 ]. In this sense, preclinical studies have focused on preventing or reversing a wide range of aging and premature aging diseases, CVD associated-CKD, using senolytic drugs [ 160 ]. However, the field is still new, and before administrating these drugs to humans, clinical trials shall be conducted.…”

Section: Unraveling Underlying Mechanisms: Therapeutical Approachesmentioning

confidence: 99%

Exploring New Kingdoms: The Role of Extracellular Vesicles in Oxi-Inflamm-Aging Related to Cardiorenal Syndrome

et al. 2021

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The incidence of age associated chronic diseases has increased in recent years. Although several diverse causes produce these phenomena, abundant evidence shows that oxidative stress plays a central role. In recent years, numerous studies have focused on elucidating the role of oxidative stress in the development and progression of both aging and chronic diseases, opening the door to the discovery of new underlying mechanisms and signaling pathways. Among them, senolytics and senomorphics, and extracellular vesicles offer new therapeutic strategies to slow the development of aging and its associated chronic diseases by decreasing oxidative stress. In this review, we aim to discuss the role of extracellular vesicles in human cardiorenal syndrome development and their possible role as biomarkers, targets, or vehicles of drugs to treat this syndrome.

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Senescence and senolytics in cardiovascular disease: Promise and potential pitfalls

Cited by 68 publications

References 181 publications

Enhanced Autophagic Flux, Suppressed Apoptosis and Reduced Macrophage Infiltration by Dasatinib in Kidneys of Obese Mice

Enhanced Autophagic Flux, Suppressed Apoptosis and Reduced Macrophage Infiltration by Dasatinib in Kidneys of Obese Mice

Inflammation, Oxidative Stress, Senescence in Atherosclerosis: Thioredoxine-1 as an Emerging Therapeutic Target

Exploring New Kingdoms: The Role of Extracellular Vesicles in Oxi-Inflamm-Aging Related to Cardiorenal Syndrome

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