Age-related alterations in the signal transduction pathways of the elastin-laminin receptor

Calcification of vascular elastin occurs in patients with arteriosclerosis, renal failure, diabetes, and vascular graft implants. We hypothesized that pathological elastin calcification is related to degenerative and osteogenic mechanisms. To test this hypothesis, the temporal expression of genes and proteins associated with elastin degradation and osteogenesis was examined in the rat subdermal calcification model by quantitative real-time reverse transcription-polymerase chain reaction and specific protein assays. Purified elastin implanted subdermally in juvenile rats exhibited progressive calcification in a time-dependent manner along with fibroblast and macrophage infiltration. Reverse transcription-polymerase chain reaction analysis showed that relative gene expression levels of matrix metalloproteinases (MMP-2 and MMP-9) and transforming growth factor-␤1 were increased in parallel with calcification. Gelatin zymography showed strong MMP activities at early time points, which were associated with high levels of soluble elastin peptides. Gene expression of core binding factor␣-1, an osteoblast-specific transcription factor, increased in parallel with elastin calcification and attained ϳ9.5-fold higher expression at 21 days compared to 3 days after implantation. Similarly, mRNA levels of the bone markers osteopontin and alkaline phosphatase also increased progressively, but osteocalcin levels remained unchanged. We conclude that degenerative and osteogenic processes may be involved in elastin calcification. (Am J

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“…53 Free calcium would then bind to calmodulin. Calmodulin has been shown to bind Smads 1 to 4 in a calcium-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Elastin Calcification in the Rat Subdermal Model Is Accompanied by Up-Regulation of Degradative and Osteogenic Cellular Responses

Lee

Basalyga

Simionescu

et al. 2006

The American Journal of Pathology

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“…Up to now, the activation of ERK1/2 by EPs has been reported in smooth muscle cells (SMCs) (Mochizuki et al, 2002), fibroblasts (Duca et al, 2002), and monocytes (Fulop et al, 2001). However, the activation of MEK1/2, the immediate upstream activator of ERK1/2, had not been reported.…”

Section: Mechanism Of Elastin Peptide-dependent Erk1/2 Activation Dismentioning

confidence: 99%

Elastin Peptides Activate Extracellular Signal-Regulated Kinase 1/2 via a Ras-Independent Mechanism Requiring Both p110γ/Raf-1 and Protein Kinase A/B-Raf Signaling in Human Skin Fibroblasts

Duca¹,

Lambert²,

Debret³

et al. 2005

Mol Pharmacol

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Elastin peptides (EPs) produced during cancer progression bind to the elastin binding protein (EBP) found at the surface of dermal fibroblasts, leading to the expression of collagenase-1 gene. The production of this enzyme involved in stromal reaction is caused by the sustained activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway via cAMP/protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K). However, the mechanism of these signaling events remains unknown. We show that -elastin (E), a commonly used EP, induces maximum phosphorylation of mitogen-activated protein kinase/extracellular signalregulated kinase (MEK)1/2 and ERK1/2 after 30 min. The simultaneous inhibition of PKA and PI3K, by N-(2-(p-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide (H89) and 2-(4-morpholynil)-8-phenyl-4H-1-bemzopyran-4-one (LY294002), respectively, blocked MEK1/2 and ERK1/2 phosphorylation, as did lactose, an EBP antagonist. E induced Raf-1 phosphorylation and activation in a PI3K-dependent manner. In our system, the PI3K p110␥ is expressed and activated by ␤␥-derived subunits from a pertussis toxin-sensitive G protein after fibroblast stimulation. Pertussis toxin also blocks the Raf-1/MEK1/2/ERK1/2 phosphorylation cascade. In addition, we found that B-Raf is expressed in dermal fibroblasts and activated in a PKA-dependent manner after E treatment, thereby integrating PKA signals to MEK1/2. It is noteworthy that Ras involvement was excluded because ERK1/2 activation by E was not blocked in RasN17-transfected fibroblasts. Together, our results identify a novel Rasindependent ERK1/2 activation system in which p110␥/Raf-1/ MEK1/2 and PKA/B-Raf/MEK1/2 cooperate to activate ERK1/2. Thus, p110␥ and B-Raf seem to be important modulators of dermal fibroblasts physiology and should now qualify as therapeutic targets in strategies aiming at limiting elastin degradation contribution to cancer progression.

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“…4 Aging is associated with an increased collagen/elastin ratio explained in part by an enhanced degradation of elastin. 5,6 Indeed, elastase activity, mainly endopeptidases, including cysteine proteases, serine proteases, and metalloproteinases, is increased with age in human aortas. 7 In the context of aging and vascular calcification, metalloproteinases, especially matrix metalloproteinases (MMPs), have been thoroughly studied.…”

mentioning

confidence: 99%

Sequential Activation of Matrix Metalloproteinase 9 and Transforming Growth Factor β in Arterial Elastocalcinosis

Bouvet

Moreau

Blanchette

et al. 2008

ATVB

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Objective-Isolated systolic hypertension is associated with increased elastase activity, vascular calcification, and vascular stiffness. We sought to determine the importance of elastase activity and matrix degradation in the development of elastocalcinosis. Methods and Results-Elastocalcinosis was induced in vivo and ex vivo using warfarin. Hemodynamic parameters, calcium deposition, elastin degradation, transforming growth factor (TGF)-␤ signaling, and elastase activity were evaluated at different time points in the in vivo model. Metalloproteinases, serine proteases, and cysteine proteases were blocked to measure their relative implication in elastin degradation. Gradual elastocalcinosis was obtained, and paralleled the elastin degradation pattern. Matrix metalloproteinase (MMP)-9 activity was increased at 5 days of warfarin treatment, whereas TGF-␤ signaling was increased at 7 days. Calcification was significantly elevated after 21 days. Blocking metalloproteinases activation with doxycycline and TGF-␤ signaling with SB-431542 were able to prevent calcification. Conclusions-Early MMP-9 activation precedes the increase of TGF-␤ signaling, and overt vascular elastocalcinosis and stiffness. Modulation of matrix degradation could represent a novel therapeutic avenue to prevent the gradual age-related stiffening of large arteries, leading to isolated systolic hypertension. Elastocalcinosis is characterized by a deposition of hydroxyapatite on the elastic lamellae of arteries. It occurs independently of atherosclerosis. 2 Until recently, it was considered as a passive process, taking place with time. However, several studies demonstrated that vascular calcification is an active phenomenon controlled by serum and matrix proteins, such as matrix Gla protein. 3 Moreover, it involves phenotypic changes of vascular smooth muscle cells with the expression of bone-related proteins. 4 Aging is associated with an increased collagen/elastin ratio explained in part by an enhanced degradation of elastin. 5,6 Indeed, elastase activity, mainly endopeptidases, including cysteine proteases, serine proteases, and metalloproteinases, is increased with age in human aortas. 7 In the context of aging and vascular calcification, metalloproteinases, especially matrix metalloproteinases (MMPs), have been thoroughly studied. Investigations on the genetic mutations of MMPs demonstrated its contribution to age-related large artery stiffening. 8,9 Furthermore, enhanced MMP-9 and MMP-2 levels and serum elastase activity were observed in patients with ISH and correlated independently with PWV. 10 In 2000, Vyavahare et al showed for the first time that elastin calcification was blunted by a site specific delivery of MMP inhibitor. 11 Moreover, Qin et al demonstrated, in an animal model, that matrix metalloproteinase inhibition with doxycycline and GM6001 decreased hydroxyapatite accumulation in the aorta. 12 These results suggest that MMPs and elastin degradation are involved in MEC.Elastin degradation induces the release of soluble elastin pep...

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Age-related alterations in the signal transduction pathways of the elastin-laminin receptor

Cited by 58 publications

References 61 publications

Elastin Calcification in the Rat Subdermal Model Is Accompanied by Up-Regulation of Degradative and Osteogenic Cellular Responses

Elastin Calcification in the Rat Subdermal Model Is Accompanied by Up-Regulation of Degradative and Osteogenic Cellular Responses

Elastin Peptides Activate Extracellular Signal-Regulated Kinase 1/2 via a Ras-Independent Mechanism Requiring Both p110γ/Raf-1 and Protein Kinase A/B-Raf Signaling in Human Skin Fibroblasts

Sequential Activation of Matrix Metalloproteinase 9 and Transforming Growth Factor β in Arterial Elastocalcinosis

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