Research article summary (published 30 Jul 1995):

Prolyl hydroxylation regulates intracellular procollagen degradation in cultured rat cardiac fibroblasts.

Full Abstract

To determine the regulatory role of prolyl hydroxylation in intracellular cardiac procollagen turnover, we examined the effects of prolyl 4-hydroxylase inhibitors (alpha, alpha-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 alpha 1(I) and alpha 1(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" pro alpha 1 (I) polypeptide into the cell culture medium, and decreased extracellular Type I collagen deposition. Similar results were obtained by treating cells with alpha, alpha-dipyridil (300 microns), and 3,4-dihydroxybenzoic acid ethyl ester (400 microM) 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 microM). Inhibition of procollagen secretion by colchicine (0.5 micrograms/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

Author information

Author/s: Eleftheriades, E G (EG); Ferguson, A G (AG); Spragia, M L (ML); Samarel, A M (AM);

Affiliation: Department of Medicine, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153, USA.

Grants: HL-43582 (Agency:NHLBI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, U.S. Gov't, P.H.S.

Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol), published in ENGLAND. (Language: eng)

Reference: 1995-Aug; vol 27 (issue 8) : pp 1459-73

Dates: Created 1996/01/22; Completed 1996/01/22; Revised 2007/11/14;

PMID: 8523410, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

2,2'-Dipyridyl - pharmacology Animals Ascorbic Acid - pharmacology Cells, Cultured Chloroquine - pharmacology Collagen - analysis; biosynthesis Enzyme Inhibitors - pharmacology Fibroblasts - drug effects; metabolism Gene Expression Heart Ventricles

Homeostasis Hydroxylation Hydroxyproline - metabolism Myocardium - metabolism Procollagen - analysis; biosynthesis; metabolism Procollagen-Proline Dioxygenase - antagonists & inhibitors Proline - metabolism RNA, Messenger - analysis; metabolism Rats Rats, Sprague-Dawley

Associated Chemicals: Enzyme Inhibitors (0) ; Procollagen (0) ; RNA, Messenger (0) ; Proline (147-85-3) ; 2,2'-Dipyridyl (366-18-7) ; Ascorbic Acid (50-81-7) ; Hydroxyproline (51-35-4) ; Chloroquine (54-05-7) ; Collagen (9007-34-5) ; Procollagen-Proline Dioxygenase (EC 1.14.11.2)

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