Increased Expression of Plasminogen Activator Inhibitor-1 with Fibrin Deposition in a Murine Model of Aging, "<i>Klotho</i>" Mouse

Takeshita, Kyosuke; Yamamoto, Kōji; Ito, Masafumi; Kondo, Takahisa; Matsushita, Tadashi; Hirai, Makoto; Kojima, Tetsuhito; Nishimura, Masahiko; Nabeshima, Yo‐ichi; Loskutoff, David J.; Saito, Hidehiko; Murohara, Toyoaki

doi:10.1055/s-2002-36699

Cited by 82 publications

(54 citation statements)

References 24 publications

(31 reference statements)

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“…Nitric oxide interferes with vascular calcification by regulating Pai1 (42). Enhanced Pai1 expression has similarly been observed in the kl/kl mice (43). However, the phenotype of the kl/kl mice and the FGF23 knockout mice results from excessive formation of 1,25(OH) 2 D 3 and subsequent hyperphosphatemia, as it is reversed by vitamin Ddeficient or low phosphate diet (27,(44)(45)(46) 2+ and phosphate concentrations, it suppresses NF-κB and TNF-α (49), which in turn are involved in the stimulation of vascular calcification (50)(51)(52).…”

Section: Figurementioning

confidence: 86%

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

et al. 2013

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Klotho is a potent regulator of 1,25-hydroxyvitamin D3 [1,25(OH) 2 D 3 ] formation and calcium-phosphate metabolism. Klotho-hypomorphic mice (kl/kl mice) suffer from severe growth deficits, rapid aging, hyperphosphatemia, hyperaldosteronism, and extensive vascular and soft tissue calcification. Sequelae of klotho deficiency are similar to those of end-stage renal disease. We show here that the mineralocorticoid receptor antagonist spironolactone reduced vascular and soft tissue calcification and increased the life span of kl/kl mice, without significant effects on 1,25(OH) 2 D 3 , FGF23, calcium, and phosphate plasma concentrations. Spironolactone also reduced the expression of osteoinductive Pit1 and Tnfa mRNA, osteogenic transcription factors, and alkaline phosphatase (Alpl) in calcified tissues of kl/kl mice. In human aortic smooth muscle cells (HAoSMCs), aldosterone dose-dependently increased PIT1 mRNA expression, an effect paralleled by increased expression of osteogenic transcription factors and enhanced ALP activity. The effects of aldosterone were reversed by both spironolactone treatment and PIT1 silencing and were mitigated by FGF23 cotreatment in HAoSMCs. In conclusion, aldosterone contributes to vascular and soft tissue calcification, an effect due, at least in part, to stimulation of spironolactone-sensitive, PIT1-dependent osteoinductive signaling.

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Section: Figurementioning

confidence: 86%

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

et al. 2013

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“…kl/kl mice exhibit a remarkable increase in plasma levels of FGF23, as well as significant increases in serum levels of calcium, phosphate, vitamin D 3 , and creatinine (13). Interestingly, kl/kl mice also have an age-dependent increase in plasma PAI-1 levels as well as increased PAI-1 expression in a number of tissues including kidney, aorta, and heart (18). Because PAI-1 is necessary and sufficient to induce replicative senescence in vitro downstream of p53 (19) and is markedly increased in kl/kl mice, we hypothesized that PAI-1 is a critical determinant of the phenotypic abnormalities developed by kl/kl mice.…”

Section: Fgf23 | Igfbp3 | Il-6 | Tm5441mentioning

confidence: 99%

PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice

Eren¹,

Boe

Murphy

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

142

124

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Cellular senescence restricts the proliferative capacity of cells and is accompanied by the production of several proteins, collectively termed the "senescence-messaging secretome" (SMS). As senescent cells accumulate in tissue, local effects of the SMS have been hypothesized to disrupt tissue regenerative capacity. Klotho functions as an aging-suppressor gene, and Klotho-deficient (kl/kl) mice exhibit an accelerated aging-like phenotype that includes a truncated lifespan, arteriosclerosis, and emphysema. Because plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor (SERPIN), is elevated in kl/kl mice and is a critical determinant of replicative senescence in vitro, we hypothesized that a reduction in extracellular proteolytic activity contributes to the accelerated aging-like phenotype of kl/kl mice. Here we show that PAI-1 deficiency retards the development of senescence and protects organ structure and function while prolonging the lifespan of kl/kl mice. These findings indicate that a SERPIN-regulated cell-nonautonomous proteolytic cascade is a critical determinant of senescence in vivo.A dvanced age contributes to the development of frailty and disease in humans, but the fundamental mechanisms that drive physiological aging are incompletely understood (1, 2). Cellular senescence, which halts the proliferative capacity of cells, is associated with the manifestation of the senescenceassociated secretory phenotype (3) and the production and secretion of a distinct set of proteins (2, 4), including insulin-like growth factor-binding proteins (IGFBPs), interleukins (ILs), transforming growth factor type β (TGF-β), and plasminogen activator inhibitor-1 (PAI-1) (5), collectively termed the "senescence-messaging secretome" (SMS) (6). In addition to this pattern of protein production and secretion, senescent cells display a distinctive morphology, and can be identified by increased expression of senescence-associated β-galactosidase (7). The tumor suppressor and proapoptotic protein p53 plays a central role in inducing replicative senescence by regulating the transcription of genes involved in cell cycle arrest and apoptosis, including the cyclindependent kinase inhibitors p16Ink4a and p21 (8). Senescence can be triggered by a number of factors, including DNA damage (9), oncogene induction (10), and oxidative stress (11). Although the relationship between cellular senescence and physiological aging remains an area of intense investigation, it is becoming increasingly evident that the two processes are fundamentally linked. Senescent cells accumulate in aging tissues and have been hypothesized to disrupt tissue regeneration, which may reflect cell-nonautonomous effects of the SMS (6).In the last decade, numerous examples of genetically modified mice with phenotypes reminiscent of human aging have been described and investigated. These include the BubR1 H/H progeroid (12) and Klotho-deficient (kl/kl) mice (13). BubR1H/H progeroid mice exhibit an age-dependent increase in the expression levels of PAI-1...

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“…Takeshita et al noted age-dependent increases in Pai1 expression and fibrin deposition in the Klotho mouse, a murine model of aging. 76 Yamamoto et al found pronounced increases in tissue factor and Pai1 gene expression in aged mice subjected to restraint stress. 77,78 By quantitating fibrin deposition and intravascular thrombosis, we have found that the factor V Leiden mouse has also been useful to elucidate prothrombotic phenotypes in mice that develop age-related vascular disease.…”

Section: Westrick Et Al Murine Models Of Vascular Thrombosis 2087mentioning

confidence: 99%

Murine Models of Vascular Thrombosis

Westrick

Winn

Eitzman

2007

ATVB

168

160

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Abstract-Thrombotic complications of vascular disease are the leading cause of morbidity and mortality in most industrialized countries. Despite this, safe and effective drugs targeting these complications are limited, especially in the chronic setting. This is because of the complexity of thrombosis in both arteries and veins, which is becoming increasingly evident as numerous factors are now known to affect the fate of a forming thrombus. To fully characterize thrombus formation in these settings, in vivo models are necessary to study the various components and intricate interactions that are involved. Genetic manipulations in mice are greatly facilitating the dissection of relevant pro-and antithrombotic influences. Standardized models for the study of thrombosis in mice as well as evolving techniques that allow imaging of molecular events during thrombus formation are now available. This review will highlight some of the recent developments in the field of thrombosis using mouse models and how these studies are expanding our knowledge of thrombotic disease. (Arterioscler Thromb Vasc

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Increased Expression of Plasminogen Activator Inhibitor-1 with Fibrin Deposition in a Murine Model of Aging, "Klotho" Mouse

Cited by 82 publications

References 24 publications

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice

Murine Models of Vascular Thrombosis

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