Upregulation of cAMP is a new functional signal pathway of Klotho in endothelial cells

Yang, Jin; Matsukawa, Naomichi; Rakugi, Hiromi; Imai, Michio; Kida, Iwao; Nagai, Michiko; Ohta, Junsuke; Fukuo, Keisuke; Nabeshima, Yo‐ichi; Ogihara, Toshio

doi:10.1016/s0006-291x(02)03056-5

Cited by 41 publications

(25 citation statements)

References 27 publications

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“…Animal studies indicated that the KLOTHO gene could protect against endothelial dysfunction (Nzietchueng et al, 2011). Yang et al (2003) reported that the KLOTHO gene might play a role in the regulation of vascular tone through a homeostatic interplay between NO and the renin-angiotensin system. This might explain the association between the KLOTHO gene and hypertension.…”

Section: Discussionmentioning

confidence: 99%

G-395A polymorphism in the promoter region of the KLOTHO gene and hypertension among elderly (90 years and older) Chinese individuals

Ll¹,

Ding²,

Dm³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to examine the possible associations between the KLOTHO G-395A gene polymorphism and hypertension in Chinese nonagenarians and centenarians. The G-395A (rs1207568) in the promoter region of the KLOTHO gene was genotyped using a standard TaqMan allelic discrimination assay. We included 710 participants aged 93.5 ± 3.2 years in the analyses. The expression of the A allele of the KLOTHO G-395A polymorphism was significantly downregulated in the hypertension group compared to the control group (0.137 vs 0.200, P < 0.001). The genotype distribution of the G-395A polymorphism between the hypertension and control groups was significantly different in women and smokers, and not in men or non-smokers. The mean systolic blood pressure, percentage of hypertension, and percentage of isolated systolic hypertension was significantly higher in the group with the GG genotype than in the group with the GA+AA genotype. Subjects expressing the GA+AA genotype demonstrated a significantly lower risk of hypertension even after adjusting for age, gender, and other relevant risk factors compared to the population expressing the GG genotype (odds ratio, 0.68; 95% confidence interval: 0.49 to 0.95).The -395A allele of the KLOTHO gene may be a protective genetic factor for hypertension in the Chinese population.

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Section: Discussionmentioning

confidence: 99%

G-395A polymorphism in the promoter region of the KLOTHO gene and hypertension among elderly (90 years and older) Chinese individuals

Ll¹,

Ding²,

Dm³

et al. 2015

Genet. Mol. Res.

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“…This study showed that PKA is involved in vascular formation process through its novel function regulating VEGF signal intensity. Various factors, such as adrenomedullin, 38 prostaglandins, 39 adiponectin, 40 ghrelin, 41 klotho, 42 and mechanical stress, especially fluid shear stress, 43 have been reported to activate PKA in ECs. We previously demonstrated that adrenomedullin could enhance EC differentiation from Flk1 ϩ cells through cAMP signaling.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of vascular progenitor potential by protein kinase A through dual induction of Flk-1 and Neuropilin-1

Yamamizu

Kawasaki

Katayama

et al. 2009

Blood

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IntroductionVascular endothelial growth factor (VEGF) signaling is a key regulator of vascular development during embryogenesis as well as neovascularization in the adult. [1][2][3] Intensity of VEGF signaling is strictly controlled during vascular development through ligandreceptor interaction. 4,5 Flk1 (also designated as VEGF receptor-2) is tyrosine-phosphorylated much more efficiently than Flt1 (VEGF receptor-1) upon VEGF binding and is thought to be the major receptor in endothelial cells (ECs) for VEGF-induced responses. [6][7][8] Whereas Flk1-null mice die at embryonic day 8.5 (E8.5) to E9.5 with no organized blood vessels, 9 Flt1-null mice die at midgestation with vascular overgrowth and disorganization. 10,11 Flt1 tyrosine kinase-deficient homozygous mice, in which VEGF can bind to the cell-surface domain of Flt1 but cannot conduct kinase signaling, developed normal vessels and survived, 12 indicating that VEGF signal intensity on Flk1 is regulated by absorption of VEGF to the higher affinity receptor, Flt1. VEGF-A heterozygotes die early in gestation due to failure in vascular system formation. 13 On the other hand, 2-to 3-fold overexpression of VEGF-A from its endogenous locus results in aberrant heart development and lethality at E12.5 to E14, 14 indicating that strictly balanced VEGF function is important in normal embryogenesis.Neuropilin-1 (NRP1) is a type 1 membrane protein, which is expressed in particular classes of developing neurons 15,16 and functions as a receptor for the class 3 semaphorins mediating semaphorin-elicited inhibitory axon guidance signals to neurons. 17,18 NRP1 is also expressed in ECs of blood vessels and endocardial cells of the heart. 15,16,19 NRP1, together with Flk1, forms a specific receptor for VEGF 165 , an isoform of VEGF, and the Flk1-VEGF 165 -NRP1 complex potently enhances Flk1 signaling. 20 Coexpression of NRP1 with Flk1 in cultured ECs enhanced VEGF 165 binding to Flk1 and VEGF-elicited mitogenic and chemotactic activities. 20 Overexpression of NRP1 in mouse embryos resulted in an excess production of blood vessels and malformed hearts. 15 NRP1-null mice die midway through gestation at E10.5 to E12.5 and exhibit defects in the heart, vasculature, and nervous system. 16 These findings indicate that NRP1 plays an important role in regulating vascular development, and Flk1/NRP1 system would be important for controlling VEGF signal intensity. However, the regulatory mechanisms of Flk1/NRP1 expression in vascular development are not fully elucidated.In the early embryo and in differentiating embryonic stem (ES) cells, Flk1 expression marks a common progenitor for both blood and endothelium. [21][22][23][24] To elucidate the mechanisms underlying vascular development, we have developed a novel ES cell differentiation system that exhibits early vascular development using Flk1 ϩ cells as common progenitors for vascular cells. 25 ES cell-derived Flk1 ϩ cells can differentiate into both ECs and mural cells (MCs: vascular smooth muscle cells and pericytes) and form mature...

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“…5 A recent genome scan for quantitative trait loci influencing HDL-C concentration identified suggestive linkage (LOD, 2.36), with a marker 360 kb 3Ј of KLOTHO, 20 providing further evidence for a role for klotho in influencing HDL-C levels. The mechanism through which klotho affects these phenotypes remains to be elucidated, although several studies have already implicated a role for klotho in the renin-angiotensin system, 10,21,22 as well as in the NO production pathway. 2,3 Analysis of the history of cardiovascular events revealed an association between KL-VS genotype and stroke.…”

Section: Discussionmentioning

confidence: 99%

“…6 Klotho has been shown to be a circulating factor detectable in serum that declines with age, 7 although recent evidence suggests that klotho may also act cell-autonomously. 8 Although the specific biological targets of klotho have not been identified, klotho likely plays a role in calcium homeostasis, 9 and klotho levels have been demonstrated to alter gene expression of angiotensin-converting enzyme (MIM 106180) 10 and plasminogen activator inhibitor type 1 (PAI-1 [MIM 173360]), 11 genes involved in CVD. 12,13 In the present population-based study of 525 Ashkenazi Jews, we used cross-sectional methods to examine the effect of the KL-VS allele on longevity, cardiovascular risk factors, and cardiovascular events.…”

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confidence: 99%

Association Between a Functional Variant of the KLOTHO Gene and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity

Arking

Atzmon

Arking

et al. 2005

Circulation Research

271

208

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Upregulation of cAMP is a new functional signal pathway of Klotho in endothelial cells

Cited by 41 publications

References 27 publications

G-395A polymorphism in the promoter region of the KLOTHO gene and hypertension among elderly (90 years and older) Chinese individuals

G-395A polymorphism in the promoter region of the KLOTHO gene and hypertension among elderly (90 years and older) Chinese individuals

Enhancement of vascular progenitor potential by protein kinase A through dual induction of Flk-1 and Neuropilin-1

Association Between a Functional Variant of the KLOTHO Gene and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity

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