Ascorbate Differentially Regulates Elastin and Collagen Biosynthesis in Vascular Smooth Muscle Cells and Skin Fibroblasts by Pretranslational Mechanisms

Davidson, Jeffrey M.; LuValle, Phyllis; Zoia, Ornella; Quaglino, Daniela; Giro, M.G.

doi:10.1074/jbc.272.1.345

Cited by 137 publications

(102 citation statements)

References 65 publications

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“…5A). Ascorbic acid treatment increases collagen production and was used as a positive control (36,(47)(48)(49). Furthermore, there was no increase in type I collagen in the detergent-insoluble ECM when CRT Ϫ/Ϫ MEFs were treated with exogenous CRT (Fig.…”

Section: ϫ/ϫmentioning

confidence: 99%

“…Ascorbic Acid Stimulates Collagen Trafficking and Deposition in CRT-deficient Cells-Ascorbic acid increases collagen transcript stabilization and is a cofactor for proline hydroxylation of procollagen, which enhances translation efficiency and secretion (36,(47)(48)(49). Because CRT Ϫ/Ϫ MEFs have apparent defects in post-translational processing of type I collagen, we investigated whether ascorbic acid can rescue these defects in the CRT Ϫ/Ϫ MEFs.…”

Section: Crt Plays a Role In Type I Collagen Retention In The Er And mentioning

confidence: 99%

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Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Graham

Sweetwyne

Pallero

et al. 2010

Journal of Biological Chemistry

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Calreticulin (CRT), a chaperone and Ca2؉ regulator, enhances wound healing, and its expression correlates with fibrosis in animal models, suggesting that CRT regulates production of the extracellular matrix. However, direct regulation of collagen matrix by CRT has not been previously demonstrated. We investigated the role of CRT in the regulation of fibrillar collagen expression, secretion, processing, and deposition in the extracellular matrix by fibroblasts. Mouse embryonic fibroblasts deficient in CRT (CRT ؊/؊ MEFs) have reduced transcript levels of fibrillar collagen I and III and less soluble collagen as compared with wild type MEFs. Correspondingly, fibroblasts engineered to overexpress CRT have increased collagen type I transcript and protein. Collagen expression appears to be regulated by endoplasmic reticulum (ER) calcium levels and intracellular CRT, because thapsigargin treatment reduced collagen expression, whereas addition of exogenous recombinant CRT had no effect. CRT ؊/؊ MEFs exhibited increased ER retention of collagen, and collagen and CRT were co-immunoprecipitated from isolated cell lysates, suggesting that CRT is important for trafficking of collagen through the ER. CRT ؊/؊ MEFs also have reduced type I procollagen processing and deposition into the extracellular matrix. The reduced collagen matrix deposition is partly a consequence of reduced fibronectin matrix formation in the CRT-deficient cells. Together, these data show that CRT complexes with collagen in cells and that CRT plays critical roles at multiple stages of collagen expression and processing. These data identify CRT as an important regulator of collagen and suggest that intracellular CRT signaling plays an important role in tissue remodeling and fibrosis.Calreticulin (CRT), 3 also known as the C1q receptor, is an endoplasmic reticulum (ER) chaperone, and a modulator of intracellular calcium signaling. CRT also is a multifunctional protein that is present in numerous cellular compartments, including the ER, cytoplasm, nucleus, at the cell surface, and as a released protein (1-5). There is evidence to suggest the involvement of CRT in tissue remodeling and wound healing. In a porcine dermal wound healing model, topical application of purified CRT increases the rate of wound healing and wound tensile strength (6). Proteomic data show up-regulation of CRT expression with fibrosis in a rat model of unilateral ureteric obstruction kidney fibrosis and in a mouse model of bleomycininduced lung fibrosis (7). The mechanisms by which CRT regulates tissue remodeling are not well understood, although fibronectin matrix deposition and modulation of cell adhesion, motility, proliferation, and matrix metalloproteinase expression have been implicated (6, 8 -13).CRT has effects on the extracellular matrix (ECM) and cellular responses to the ECM. Fibroblasts overexpressing CRT have increased fibronectin mRNA, protein, and matrix deposition, and cells lacking CRT express less fibronectin than wild type cells (9,14). CRT in the ER is thought to reg...

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Section: ϫ/ϫmentioning

confidence: 99%

Section: Crt Plays a Role In Type I Collagen Retention In The Er And mentioning

confidence: 99%

Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Graham

Sweetwyne

Pallero

et al. 2010

Journal of Biological Chemistry

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“…Of note, opposing trends in collagen and elastic matrix generation were observed in this study and in others. 42,82,88 Despite increased elastic matrix deposition on the 3D electrospun PCL scaffolds described above, compared to 2D tissue culture plastic, no corresponding differences were noted in the mRNA expression of matrix proteins. This suggests that substrate chemistry, surface topography, and surface compliance (i.e., the ability to be deformed) can in certain cases influence post-transcriptional mechanisms of tropoelastin recruitment and crosslinking without impacting elastin gene expression itself.…”

Section: D Versus 3d Substratesmentioning

confidence: 97%

“…This signaling leads to physiological outcomes such as enhanced or inhibited elastic matrix synthesis. Prior studies have shown that elastin matrix synthesis is regulated by numerous biochemical factors that may be broadly classified as elastin synthesis inhibitors (e.g., ascorbic acid, 42 basic fibroblast growth factor 43 , cyclic AMP 44 , and monensin 45 ) and elastin synthesis stimulators (e.g., cyclic GMP, 44 fetal calf serum, 46 insulin-like growth factor 1 [IGF-1], 47,48 and transforming growth factor b1 [TGFb1]…”

Section: Elastin In Vascular Tissue Engineering 205 Elastogenic Stimumentioning

confidence: 99%

Tissue Engineering and Regenerative Strategies to Replicate Biocomplexity of Vascular Elastic Matrix Assembly

Bashur

Venkataraman

Ramamurthi

2012

Tissue Engineering Part B: Reviews

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“…It is necessary for VSMC collagen synthesis, since without it (Schwartz et al, 1982), or in the presence of the non-functional ascorbate analog ethyl-3,4-dihydroxybenzoate (Sasaki et al, 1987), VSMCs form little collagen. In addition to enhancing post-translational collagen modification in VSMCs, ascorbate also increases procollagen synthesis by a pre-translational mechanism (Barone et al, 1985;Davidson et al, 1997). Although collagen synthesis is required for VSMC migration and proliferation (Ivanov et al, 1997;Rocnik et al, 1998), the overall effect of ascorbate on these processes seems to be the opposite.…”

Section: Vascular Smooth Muscle Cellsmentioning

confidence: 99%

Inflammation in the vascular bed: Importance of vitamin C

Aguirre

May

2008

Pharmacology & Therapeutics

110

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Despite decreases in atherosclerotic coronary vascular disease over the last several decades, atherosclerosis remains a major cause of mortality in developed nations. One possible contributor to this residual risk is oxidant stress, which is generated by the inflammatory response of atherosclerosis. Although there is a wealth of in vitro, cellular, and animal data supporting a protective role for antioxidant vitamins and nutrients in the atherosclerotic process, the best clinical trials have been negative. This may be due to the fact that antioxidant therapies are applied "too little and too late." This review considers the role of vitamin C, or ascorbic acid in preventing the earliest inflammatory changes in atherosclerosis. It focuses on the three major vascular cell types involved in atherosclerosis: endothelial cells, vascular smooth muscle cells, and macrophages. Ascorbate chemistry, recycling, and function are described for these cell types, with emphasis on whether and how the vitamin might affect the inflammatory process. For endothelial cells, ascorbate helps to prevent endothelial dysfunction, stimulates type IV collagen synthesis, and enhances cell proliferation. For vascular smooth muscle cells, ascorbate inhibits dedifferentiation, recruitment, and proliferation in areas of vascular damage. For macrophages, ascorbate decreases oxidant stress related to their activation, decreases uptake and degradation of oxidized LDL in some studies, and enhances several aspects of their function. Although further studies of ascorbate function in these cell types and in novel animal models are needed, available evidence generally supports a salutary role for this vitamin in ameliorating the earliest stages of atherosclerosis.

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Ascorbate Differentially Regulates Elastin and Collagen Biosynthesis in Vascular Smooth Muscle Cells and Skin Fibroblasts by Pretranslational Mechanisms

Cited by 137 publications

References 65 publications

Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Tissue Engineering and Regenerative Strategies to Replicate Biocomplexity of Vascular Elastic Matrix Assembly

Inflammation in the vascular bed: Importance of vitamin C

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