Prolyl hydroxylation regulates intracellular procollagen degradation in cultured rat cardiac fibroblasts
Identifieur interne : 002C02 ( Main/Merge ); précédent : 002C01; suivant : 002C03Prolyl hydroxylation regulates intracellular procollagen degradation in cultured rat cardiac fibroblasts
Auteurs : Elias G. Eleftheriades [États-Unis] ; Alan G. Ferguson [États-Unis] ; M. Lisa Spragia [États-Unis] ; Allen M. Samarel [États-Unis]Source :
- Journal of Molecular and Cellular Cardiology [ 0022-2828 ] ; 1995.
English descriptors
- KwdEn :
- Teeft :
- Acid ethyl ester, Acidic, Acidic intracellular compartments, Anova, Ascorbate, Ascorbate deficiency, Ascorbic, Ascorbic acid, Ascorbic acid deficiency, Band intensity, Biochem, Biol chem, Cardiac, Cardiac fibroblast procollagen metabolism, Cardiac fibroblasts, Cardiac interstitium, Cdna, Cdna probes, Cell monolayer, Cell monolayers, Chloroquine, Colchicine, Collagen, Collagen antibody, Collagen deposition, Collagen metabolism, Collagen production, Culture medium, Cultured, Daily medium replacement, Degradation, Different experiments, Eleftheriades, Ester, Ethanol, Ethanol precipitation, Ethyl ester, Extracellular, Extracellular matrix, Fibrillar, Fibrillar collagens, Fibroblast, Heart fibroblasts, Hemodynamic overload, Hydroxylation, Hydroxyproline, Intracellular, Intracellular accumulation, Intracellular degradation, Matrix, Metabolism, Monolayer, Monolayers, Mrna, Mrna levels, Neonatal, Peptidyl, Peptidyl hydroxyproline synthesis, Polypeptide, Procollagen, Procollagen intracellular transport, Procollagen metabolism, Procollagen polypeptides, Procollagen synthesis, Procollagens, Prolyl, Prolyl hydroxylation, Prolyl residues, Significant reduction, Total amount, Underhydroxylated, Underhydroxylated procollagens.
Abstract
To determine the regulatory role of prolyl hydroxylation in intracellular cardiac procollagen turnover, we examined the effects of prolyl 4-hydroxylase inhibitors (α,α′-dipyridil, 3,4-dihydroxybenzoic acid ethyl ester, pyridine 2,4-dicarboxylic acid ethyl ester) and ascorbic acid on procollagen metabolism by cultured, neonatal rat cardiac fibroblasts. Ascorbate-deficient fibroblasts showed decreased rates of prolyl hydroxylation and total collagen accumulation without a significant reduction in α1(I) and α1(III) mRNA levels. The fraction of newly synthesized procollagens degraded intracellularly was also substantially increased in ascorbate-deficient cells (50±7 v 30±3% in ascorbate-deficient v control fibroblasts; P<0.05). These findings were associated with increased intracellular accumulation of Type I procollagen, enhanced secretion of “underhydroxylated” proα1(I) polypeptide into the cell culture medium, and decreased extracellular Type I collagen deposition. Similar results were obtained by treating cells with α,α′-dipyridil (300 μm), and 3,4-dihydroxybenzoic acid ethyl ester (400 μm) in the presence of ascorbate. A major portion of the enhanced degradation of newly synthesized procollagens occurred within acidic intracellular compartments as indicated by the inhibition of procollagen degradation by chloroquine (25 μm). Inhibition of procollagen secretion by colchicine (0.5 μg/ml) enhanced the diversion to, and subsequent intracellular degradation of underhydroxylated procollagens in cardiac fibroblast lysosomes. We conclude that inactivation of prolyl 4-hydroxylase increases intracellular accumulation and intralysosomal degradation of newly synthesized cardiac procollagen polypeptides. These observations suggest that procollagen prolyl hydroxylation may be important in the regulation of collagen accumulation by cardiac interstitial cells during fibrotic processes in vivo.
Url:
DOI: 10.1016/S0022-2828(95)90095-0
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<term>Extracellular matrix</term>
<term>Fibrosis</term>
<term>Oxoglutarate</term>
<term>Prolyl 4-hydroxylase</term>
<term>Protein degradation</term>
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<keywords scheme="Teeft" xml:lang="en"><term>Acid ethyl ester</term>
<term>Acidic</term>
<term>Acidic intracellular compartments</term>
<term>Anova</term>
<term>Ascorbate</term>
<term>Ascorbate deficiency</term>
<term>Ascorbic</term>
<term>Ascorbic acid</term>
<term>Ascorbic acid deficiency</term>
<term>Band intensity</term>
<term>Biochem</term>
<term>Biol chem</term>
<term>Cardiac</term>
<term>Cardiac fibroblast procollagen metabolism</term>
<term>Cardiac fibroblasts</term>
<term>Cardiac interstitium</term>
<term>Cdna</term>
<term>Cdna probes</term>
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<term>Cell monolayers</term>
<term>Chloroquine</term>
<term>Colchicine</term>
<term>Collagen</term>
<term>Collagen antibody</term>
<term>Collagen deposition</term>
<term>Collagen metabolism</term>
<term>Collagen production</term>
<term>Culture medium</term>
<term>Cultured</term>
<term>Daily medium replacement</term>
<term>Degradation</term>
<term>Different experiments</term>
<term>Eleftheriades</term>
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<term>Ethanol</term>
<term>Ethanol precipitation</term>
<term>Ethyl ester</term>
<term>Extracellular</term>
<term>Extracellular matrix</term>
<term>Fibrillar</term>
<term>Fibrillar collagens</term>
<term>Fibroblast</term>
<term>Heart fibroblasts</term>
<term>Hemodynamic overload</term>
<term>Hydroxylation</term>
<term>Hydroxyproline</term>
<term>Intracellular</term>
<term>Intracellular accumulation</term>
<term>Intracellular degradation</term>
<term>Matrix</term>
<term>Metabolism</term>
<term>Monolayer</term>
<term>Monolayers</term>
<term>Mrna</term>
<term>Mrna levels</term>
<term>Neonatal</term>
<term>Peptidyl</term>
<term>Peptidyl hydroxyproline synthesis</term>
<term>Polypeptide</term>
<term>Procollagen</term>
<term>Procollagen intracellular transport</term>
<term>Procollagen metabolism</term>
<term>Procollagen polypeptides</term>
<term>Procollagen synthesis</term>
<term>Procollagens</term>
<term>Prolyl</term>
<term>Prolyl hydroxylation</term>
<term>Prolyl residues</term>
<term>Significant reduction</term>
<term>Total amount</term>
<term>Underhydroxylated</term>
<term>Underhydroxylated procollagens</term>
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<front><div type="abstract" xml:lang="en">To determine the regulatory role of prolyl hydroxylation in intracellular cardiac procollagen turnover, we examined the effects of prolyl 4-hydroxylase inhibitors (α,α′-dipyridil, 3,4-dihydroxybenzoic acid ethyl ester, pyridine 2,4-dicarboxylic acid ethyl ester) and ascorbic acid on procollagen metabolism by cultured, neonatal rat cardiac fibroblasts. Ascorbate-deficient fibroblasts showed decreased rates of prolyl hydroxylation and total collagen accumulation without a significant reduction in α1(I) and α1(III) mRNA levels. The fraction of newly synthesized procollagens degraded intracellularly was also substantially increased in ascorbate-deficient cells (50±7 v 30±3% in ascorbate-deficient v control fibroblasts; P<0.05). These findings were associated with increased intracellular accumulation of Type I procollagen, enhanced secretion of “underhydroxylated” proα1(I) polypeptide into the cell culture medium, and decreased extracellular Type I collagen deposition. Similar results were obtained by treating cells with α,α′-dipyridil (300 μm), and 3,4-dihydroxybenzoic acid ethyl ester (400 μm) in the presence of ascorbate. A major portion of the enhanced degradation of newly synthesized procollagens occurred within acidic intracellular compartments as indicated by the inhibition of procollagen degradation by chloroquine (25 μm). Inhibition of procollagen secretion by colchicine (0.5 μg/ml) enhanced the diversion to, and subsequent intracellular degradation of underhydroxylated procollagens in cardiac fibroblast lysosomes. We conclude that inactivation of prolyl 4-hydroxylase increases intracellular accumulation and intralysosomal degradation of newly synthesized cardiac procollagen polypeptides. These observations suggest that procollagen prolyl hydroxylation may be important in the regulation of collagen accumulation by cardiac interstitial cells during fibrotic processes in vivo.</div>
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