FOXOs and Sirtuins in Vascular Growth, Maintenance, and Aging

Oellerich, Mark F.; Potente, Michael

doi:10.1161/circresaha.111.246488

Cited by 134 publications

(133 citation statements)

References 140 publications

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“…With regards to the circulatory system, KO of FOXO1 is embryo-lethal due to vessel malformation while conditional KO in adults causes hemangiomas and angiosarcomas due to unchecked proliferation of angiogenic cells. For FOXO3, KO phenotypes are more subtle, but enhanced vessel growth is seen with hypoxia (1326). Control of excess proliferation is exerted by FOXO1/3 through both apoptosis and cell cycle regulatory genes.…”

Section: Lpin1mentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

379

355

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Section: Lpin1mentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

379

355

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“…Similarly, SIRT1 regulates vessel branching by deacetylating FOXO1, a transcription factor that inhibits endothelial angiogenic activity (Eijkelenboom and Burgering, 2013). FOXO1 deficiency causes abnormal vascular branching that leads to embryonic lethality, demonstrating that metabolic signals can intricately regulate vascular branching (Furuyama et al, 2004;Oellerich and Potente, 2012).…”

Section: Glycogen Metabolismmentioning

confidence: 99%

Angiogenesis revisited – role and therapeutic potential of targeting endothelial metabolism

Stapor

Wang

Goveia

et al. 2014

Journal of Cell Science

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Clinically approved therapies that target angiogenesis in tumors and ocular diseases focus on controlling pro-angiogenic growth factors in order to reduce aberrant microvascular growth. Although research on angiogenesis has revealed key mechanisms that regulate tissue vascularization, therapeutic success has been limited owing to insufficient efficacy, refractoriness and tumor resistance. Emerging concepts suggest that, in addition to growth factors, vascular metabolism also regulates angiogenesis and is a viable target for manipulating the microvasculature. Recent studies show that endothelial cells rely on glycolysis for ATP production, and that the key glycolytic regulator 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase 3 (PFKFB3) regulates angiogenesis by controlling the balance of tip versus stalk cells. As endothelial cells acquire a tip cell phenotype, they increase glycolytic production of ATP for sprouting. Furthermore, pharmacological blockade of PFKFB3 causes a transient, partial reduction in glycolysis, and reduces pathological angiogenesis with minimal systemic harm. Although further assessment of endothelial cell metabolism is necessary, these results represent a paradigm shift in anti-angiogenic therapy from targeting angiogenic factors to focusing on vascular metabolism, warranting research on the metabolic pathways that govern angiogenesis.

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“…In contrast, it is generally accepted that a higher activity of sirtuins is associated with protection against the majority of age-related diseases such as type 2 diabetes, cardiovascular disease, and Alzheimer's disease. [15][16][17][18] Notably, a calorie restriction diet (CR), the only intervention known so far to extend healthspan and lifespan, leads to SIRT1 and SIRT3 overexpression. 19,20 It has been also shown that SIRT1 transgenic mice present features similar to those of animals fed a CR: they are lean, resistant to cancer, as well as to the diet-induced metabolic syndrome.…”

Section: Introductionmentioning

confidence: 99%

miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans

Owczarz

Budzinska

Domaszewska-Szostek

et al. 2017

Exp Biol Med (Maywood)

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Impact statementHigh expression of sirtuins, particularly SIRT1, lowers the risk of age-related diseases and probably slows down the rate of aging; therefore, their sustained expression should be one of the features of longevity. However, in this work we show that in peripheral blood mononuclear cells (PBMC) of long-lived individuals, expression of majority of the SIRT genes is significantly lower than in cells of young study subjects. In long-lived individuals, downregulation of SIRT1 coexists with upregulation of SIRT1 mRNA-interacting miR-34a and miR-9, indicating the role of epigenetic drift in age-dependent deregulation of SIRT1 expression. Such constellation of SIRT1, miR-34a, and miR-9 expression in PBMC of successfully aging long-lived individuals indicates that, at least in these individuals, it is not a risk factor for morbidity and mortality. It might however affect the function of the immune system and, therefore, aging individuals can profit from interventions increasing the level of SIRT1. AbstractIncreased expression of sirtuins lowers the risk of age-related diseases, while their role in the regulation of longevity is not firmly established. Since aging is associated with immunosenescence, we tested whether sirtuin expression was modified in peripheral blood mononuclear cells (PBMC) in an age-related manner and whether this might result from altered expression of the selected miRNAs. The expression of seven SIRT genes and of SIRT1 mRNA-interacting miR-9, miR-34a, miR-132, and miR-199a-5p was evaluated by real-time PCR in PBMC originating from young (Y, n ¼ 57, mean age 27 AE 4.3 years), elderly (E, n ¼ 52, 65 AE 3.4 years), and long-lived (L, n ¼ 56, 94 AE 3.5 years) individuals. Older age was associated with a decreased expression of the majority of the SIRT genes. Most severely affected were median expressions of SIRT1 (P ¼ 0.000001 for the whole studied group, Y vs. E: P < 0.000001, Y vs. L: P < 0.000001), and of SIRT3 (P ¼ 0.000001, Y vs. E: P ¼ 0.000004, Y vs. L: P ¼ 0.000028). Older age was also associated with the increased median expression of miR-34a (P ¼ 0.000001, Y vs. E: P ¼ 0.001, Y vs. L: P ¼ 0.000004) and of miR-9 (P ¼ 0.05, Y vs. L: P ¼ 0.054). In functional studies, miR-9 interacted with the 3 0 UTR of SIRT1 mRNA. The SIRT1 mRNA level negatively correlated with the expression of miR34a (r ¼ À0.234, P ¼ 0.003). In conclusion, age-related decrease of SIRT1 expression in PBMC might in part result from overexpression of miR-34a and miR-9. In addition, the sustained expression of the SIRT genes in PBMC is not a prerequisite to longevity in humans but might be one of the reasons for the immune system dysfunction in the elderly.

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FOXOs and Sirtuins in Vascular Growth, Maintenance, and Aging

Cited by 134 publications

References 140 publications

Molecular Biology of Atherosclerosis

Molecular Biology of Atherosclerosis

Angiogenesis revisited – role and therapeutic potential of targeting endothelial metabolism

miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans

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