Plasminogen activator inhibitor-1 is a major stress-regulated gene: Implications for stress-induced thrombosis in aged individuals

Yamamoto, Kōji; Takeshita, Kyosuke; Shimokawa, Takayoshi; Yi, Hong; Isobe, Ken‐ichi; Loskutoff, David J.; Saito, Hidehiko

doi:10.1073/pnas.022608799

Cited by 145 publications

(137 citation statements)

References 51 publications

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“…[25][26][27][28] First, in spns1 hi891/ hi891 fish embryos, our qRT-PCR experiments showed that the expression of glb1 was more than 2-fold enhanced, and serpine1/pai-1 expression, which can also be elevated in cellular and organismal senescence, [29][30][31] became more than 3-fold through 8-fold higher, with the advancing opaque yolk phenotype ( Fig. 6A and B).…”

Section: Concurrent Heritable Defects Of Both Spns1 and Atp6v0ca In Zmentioning

confidence: 97%

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

et al. 2016

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Spns1 (Spinster homolog 1 [Drosophila]) in vertebrates, as well as Spin (Spinster) in Drosophila, is a hypothetical lysosomal H C -carbohydrate transporter, which functions at a late stage of macroautophagy (hereafter autophagy). The Spin/Spns1 defect induces aberrant autolysosome formation that leads to developmental senescence in the embryonic stage and premature aging symptoms in adulthood. However, the molecular mechanism by which loss of Spin/Spns1 leads to the specific pathogenesis remains to be elucidated. Using chemical, genetic and CRISPR/Cas9-mediated genome-editing approaches in zebrafish, we investigated and determined a mechanism that suppresses embryonic senescence as well as autolysosomal impairment mediated by Spns1 deficiency. Unexpectedly, we found that a concurrent disruption of the vacuolar-type H C -ATPase (v-ATPase) subunit gene, atp6v0ca (ATPase, H C transporting, lysosomal, V0 subunit ca) led to suppression of the senescence induced by the Spns1 defect, whereas the sole loss of Atp6v0ca led to senescent embryos similar to the single spns1 mutation. Moreover, we discovered that the combined stable defect seen in the presence of both the spns1 and atp6v0ca mutant genes still subsequently induced premature autophagosome-lysosome fusion marked by insufficient acidity, while extending developmental life span, compared with the solely mutated spns1 defect. Our data suggest that Spns1 and the v-ATPase orchestrate proper autolysosomal biogenesis with optimal acidification that is critically linked to developmental senescence and survival.

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Section: Concurrent Heritable Defects Of Both Spns1 and Atp6v0ca In Zmentioning

confidence: 97%

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

et al. 2016

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“…1 Restraint stress was induced as described previously. 3 The mice were individually housed in a room at 23Ϯ1°C on a 14/10-hour lighting schedule. Each mouse was acclimated for 1 week before initiation of restraint stress at 6 weeks.…”

Section: In Vivo Study Of Klotho Mutant Micementioning

confidence: 99%

Sinoatrial Node Dysfunction and Early Unexpected Death of Mice With a Defect of klotho Gene Expression

Takeshita¹,

Fujimori²,

Kurotaki³

et al. 2004

Circulation

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197

144

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Background-Homozygous mutant mice with a defect of klotho gene expression (kl/kl) show multiple age-related disorders and premature death from unknown causes. Methods and Results-The kl/kl mice subjected to 20-hour restraint stress showed a high rate (20/30) of sudden death, which was associated with sinoatrial node dysfunction (conduction block or arrest). Heart rate and plasma norepinephrine of kl/kl mice, unlike those of wild-type (WT) mice, failed to increase during the stress. Intrinsic heart rate after pharmacological blockade of autonomic nerves in kl/kl mice was significantly lower than that in WT mice (380Ϯ33 versus 470Ϯ44 bpm; nϭ7). The sinus node recovery time after an overdrive pacing (600 bpm, 30 seconds) in kl/kl mice was significantly longer than in WT mice (392Ϯ37 versus 233Ϯ24 ms; nϭ6). In isolated sinoatrial node preparations, the positive chronotropic effect of isoproterenol was significantly less, whereas the negative chronotropic effect of acetylcholine was significantly greater in kl/kl than in WT mice. There was no degenerative structural change in the sinoatrial node of kl/kl mice. The precise localization of klotho was analyzed in newly prepared klotho-null mice with a reporter gene system (kl Ϫgeo ). Homozygous kl Ϫgeo mice showed characteristic age-associated phenotypes that were almost identical to those of kl/kl mice. In the kl Ϫgeo mice, klotho expression was recognized exclusively in the sinoatrial node region in the heart in addition to parathyroid, kidney, and choroid plexus. Conclusions-In the heart, klotho is expressed solely at the sinoatrial node. klotho gene expression is essential for the sinoatrial node to function as a dependable pacemaker under conditions of stress.

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“…Additionally, some reports have shown that SNA induced enhancement of PAI-1 mRNA, and increased PAI-1 activity. [24][25][26] More importantly, PAI-1 expression is dramatically enhanced in aged mice. In humans, elevation of PAI-1 levels occurs in several thrombotic conditions in atherosclerotic patients and aged subjects.…”

Section: Discussionmentioning

confidence: 99%

Altered Interaction Between Plasminogen Activator Inhibitor Type 1 Activity and Sympathetic Nerve Activity With Aging

Otowa

Takamura

Murai

et al. 2008

Circ J

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The study population comprised 16 young healthy subjects (all men: aged between 21 and 37 years, mean age 26.1 years) and 10 aged subjects (9 men, 1 woman; aged between 46 and 71 years, mean age 56.9 years). All aged subjects Circ J 2008; 72: 458 -462 (Received July 11, 2007; revised manuscript received October 16, 2007; accepted November 1, 2007 Background It has been reported that sympathetic nerve activity (SNA) is associated with fibrinolysis, but the interaction between SNA and the fibrinolytic system with aging has not been elucidated in humans. The purpose of this study was to examine the effect of age-related SNA on the activity of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (tPA) using muscle SNA (MSNA). Methods and ResultsThis study included 16 young subjects (mean age 26.1 years) and 10 aged subjects (mean age 56.9 years). Lower body negative pressure (LBNP) was performed at -40 mmHg for 30 min. LBNP significantly increased both tPA and PAI-1 activity (from 5.2±0.5 to 7.3±1.2 IU/ml and from 2.85±0.68 to 4.06± 0.73 U/ml, p<0.01, respectively) in the aged group. In the young group, tPA activity tended to increase, whereas PAI-1 activity was unchanged. There was a correlation between MSNA and PAI-1 activity in the aged group (r=0.47, p<0.01).Conclusions SNA in an aging subject leads to an increase in the activity of PAI-1, which indicates that an altered interaction between SNA and PAI-1 activity contributes to increased cardiovascular events in the elderly population. (Circ J 2008; 72: 458 -462)

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Plasminogen activator inhibitor-1 is a major stress-regulated gene: Implications for stress-induced thrombosis in aged individuals

Cited by 145 publications

References 51 publications

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

Sinoatrial Node Dysfunction and Early Unexpected Death of Mice With a Defect of klotho Gene Expression

Altered Interaction Between Plasminogen Activator Inhibitor Type 1 Activity and Sympathetic Nerve Activity With Aging

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