Cellular senescence evaluated by P16INK4a immunohistochemistry is a prevalent phenomenon in advanced calcific aortic valve disease

Oh, Kei Shing; Febres‐Aldana, Christopher A.; Kuritzky, Nicholas; Ujueta, Francisco; Arenas, Ivan A.; Sriganeshan, Vathany; Medina, Ana Maria; Poppiti, Robert

doi:10.1016/j.carpath.2021.107318

Cited by 8 publications

(8 citation statements)

References 27 publications

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“…In addition, CEC from young or aged mice were stained with antibodies against γH2AX and p16 INK4a . γH2AX is a marker of double-strand breaks, the most severe form of DNA damage ( Noubissi et al, 2021 ); and p16 INK4a is a tumor suppressor, overexpression of which is associated with cell cycle arrest and cell senescence ( Oh et al, 2021 ). Aged CEC exhibited higher levels of both the DNA damage marker γH2AX ( Figures 1C,D ) and the tumor suppressor p16 INK4a ( Figures 1E,F ), compared with young cells.…”

Section: Resultsmentioning

confidence: 99%

G-quadruplexes Stabilization Upregulates CCN1 and Accelerates Aging in Cultured Cerebral Endothelial Cells

et al. 2022

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Senescence in the cerebral endothelium has been proposed as a mechanism that can drive dysfunction of the cerebral vasculature, which precedes vascular dementia. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) is a matricellular protein secreted by cerebral endothelial cells (CEC). CCN1 induces senescence in fibroblasts. However, whether CCN1 contributes to senescence in CEC and how this is regulated requires further study. Aging has been associated with the formation of four-stranded Guanine-quadruplexes (G4s) in G-rich motifs of DNA and RNA. Stabilization of the G4 structures regulates transcription and translation either by upregulation or downregulation depending on the gene target. Previously, we showed that aged mice treated with a G4-stabilizing compound had enhanced senescence-associated (SA) phenotypes in their brains, and these mice exhibited enhanced cognitive deficits. A sequence in the 3′-UTR of the human CCN1 mRNA has the ability to fold into G4s in vitro. We hypothesize that G4 stabilization regulates CCN1 in cultured primary CEC and induces endothelial senescence. We used cerebral microvessel fractions and cultured primary CEC from young (4-months old, m/o) and aged (18-m/o) mice to determine CCN1 levels. SA phenotypes were determined by high-resolution fluorescence microscopy in cultured primary CEC, and we used Thioflavin T to recognize RNA-G4s for fluorescence spectra. We found that cultured CEC from aged mice exhibited enhanced levels of SA phenotypes, and higher levels of CCN1 and G4 stabilization. In cultured CEC, CCN1 induced SA phenotypes, such as SA β-galactosidase activity, and double-strand DNA damage. Furthermore, CCN1 levels were upregulated by a G4 ligand, and a G-rich motif in the 3′-UTR of the Ccn1 mRNA was folded into a G4. In conclusion, we demonstrate that CCN1 can induce senescence in cultured primary CEC, and we provide evidence that G4 stabilization is a novel mechanism regulating the SASP component CCN1.

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Section: Resultsmentioning

confidence: 99%

G-quadruplexes Stabilization Upregulates CCN1 and Accelerates Aging in Cultured Cerebral Endothelial Cells

et al. 2022

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“…These same studies additionally demonstrate that elimination of senescent SMCs from atherosclerotic aortas also reduced both aortic calcification and the expression of osteogenic signalling in the aortas of hypercholesterolemic aged mice ( Roos et al, 2016 ), data which implicates senolytics as potential therapies for calcific aortic valve disease (CAVD) which is also associated with increased aortic senescence ( Oh et al, 2021 ). CAVD affects more than 5.2 million people in the US and the only effective treatment is valve replacement, this now being the second most prevalent cause for heart surgery annually in North America ( Lerman et al, 2015 ), which is not guaranteed to have long-term success ( Dutta and Lincoln, 2018 ).…”

Section: Atherosclerosis and The Potential To Treat Thoracic Aortic Aneurysms And Calcific Aortic Valve Diseasementioning

confidence: 88%

“…CAVD is an age-related calcifying degenerative disorder of the valve leaflets which is prevalent in the ageing population. Senescent VSMCs are now thought to drive CAVD, as there is an accumulation of senescent VSMC, determined by p16 inka and p53-positive expression, in the aortic valves of individuals with advanced CAVD ( Oh et al, 2021 ). Furthermore, these senescent VSMCs overexpress proteins that promote osteoblastic transdifferentiation including RUNX-2, alkaline phosphatase type I collagen and BMP-2 which are postulated to promote calcification and fibrosis, and there is a direct correlation between tissue remodelling severity in the aortic valve and the levels of senescent marker expression in the aorta ( Burton et al, 2010 ).…”

Section: Atherosclerosis and The Potential To Treat Thoracic Aortic Aneurysms And Calcific Aortic Valve Diseasementioning

confidence: 99%

Senescence and senolytics in cardiovascular disease: Promise and potential pitfalls

Owens

Walaszczyk

Spyridopoulos

et al. 2021

Mechanisms of Ageing and Development

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Highlights Studies have demonstrated that senescence contributes to the pathophysiology of several age-related cardiovascular diseases. Senolytics eliminate senescent cells in cardiovascular tissues and prevent or reverse disease progression. While this data is encouraging, questions remain regarding the potential short and long-term detrimental effects of senolytic mediated apoptosis.

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“…However, aging rarely leads to severe aortic valve stenosis, as a significant proportion of the elderly population does not develop significant AS. In addition to aging, excessive mechanical stress, genetic factors and metabolic factors, such as high blood pressure, overweight and hypercholesterinemia, can induce and aggravate pathological cell senescence and calcification [ 36 , 37 ]. Excessive mechanical stress is present in the case of increasing aortic stenosis severity when the blood flow is oscillatory on the aortic side and turbulent on the ventricular side.…”

Section: Pathomechanism Of Aortic Valve Calcification: Senescence And...mentioning

confidence: 99%

“…It is proposed that besides aging, cardiovascular risk factors, such as hypertension, diabetes, hyperlipidemia and smoking can influence the number of circulating endothelial progenitor cells and the regenerative capacity of the cardiovascular system, including the vascular system and the valves [ 39 , 40 ]. Molecular markers of cellular senescence, such as beta-galactosidase and cell cycle arrest inductor P16INK4A (inhibitor of cyclin D-dependent kinases), have shown a correlation with tissue remodeling severity and degenerative changes in the aortic valve [ 37 ].…”

Section: Pathomechanism Of Aortic Valve Calcification: Senescence And...mentioning

confidence: 99%

Cellular Senescence, Aging and Non-Aging Processes in Calcified Aortic Valve Stenosis: From Bench-Side to Bedside

Molnár

Pásztor

Merkely

2022

Cells

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Aortic valve stenosis (AS) is the most common valvular heart disease. The incidence of AS increases with age, however, a significant proportion of elderly people have no significant AS, indicating that both aging and nonaging pathways are involved in the pathomechanism of AS. Age-related and stress-induced cellular senescence accompanied by further active processes represent the key elements of AS pathomechanism. The early stage of aortic valve degeneration involves dysfunction and disruption of the valvular endothelium due to cellular senescence and mechanical stress on blood flow. These cells are replaced by circulating progenitor cells, but in an age-dependent decelerating manner. When endothelial denudation is no longer replaced by progenitor cells, the path opens for focal lipid deposition, initiating subsequent oxidation, inflammation and micromineralisation. Later stages of AS feature a complex active process with extracellular matrix remodeling, fibrosis and calcification. Echocardiography is the gold standard method for diagnosing aortic valve disease, although computed tomography and cardiac magnetic resonance are useful additional imaging methods. To date, no medical treatment has been proven to halt the progression of AS. Elucidation of differences and similarities between vascular and valvular calcification pathomechanisms may help to find effective medical therapy and reduce the increasing health burden of the disease.

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Cellular senescence evaluated by P16INK4a immunohistochemistry is a prevalent phenomenon in advanced calcific aortic valve disease

Cited by 8 publications

References 27 publications

G-quadruplexes Stabilization Upregulates CCN1 and Accelerates Aging in Cultured Cerebral Endothelial Cells

G-quadruplexes Stabilization Upregulates CCN1 and Accelerates Aging in Cultured Cerebral Endothelial Cells

Senescence and senolytics in cardiovascular disease: Promise and potential pitfalls

Cellular Senescence, Aging and Non-Aging Processes in Calcified Aortic Valve Stenosis: From Bench-Side to Bedside

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