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PubMed2025

Pitavastatin, Procollagen Pathways, and Plaque Stabilization in Patients With HIV: A Secondary Analysis of the REPRIEVE Randomized Clinical Trial.

IMPORTANCE: In a mechanistic substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) randomized clinical trial, pitavastatin reduced noncalcified plaque (NCP) volume, but specific protein and gene pathways contributing to changes in coronary plaque remain unknown. OBJECTIVE: To use targeted discovery proteomics and transcriptomics approaches to interrogate biological pathways beyond low-density lipoprotein cholesterol (LDL-C), relating statin outcomes to reduce NCP volume and promote plaque stabilization among people with HIV (PWH). DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of the double-blind, placebo-controlled, REPRIEVE randomized clinical trial. Participants underwent coronary computed tomography angiography (CTA), plasma protein analysis, and transcriptomic analysis at baseline and 2-year follow-up. The trial enrolled PWH from April 2015 to February 2018 at 31 US research sites. PWH without known cardiovascular diseases taking antiretroviral therapy and with low to moderate 10-year cardiovascular risk were eligible. Data analyses were conducted from October 2023 to February 2024. INTERVENTION: Oral pitavastatin calcium, 4 mg per day. MAIN OUTCOMES AND MEASURES: Relative change in plasma proteomics, transcriptomics, and noncalcified plaque volume among those receiving treatment vs placebo. RESULTS: Among 558 individuals (mean [SD] age, 51 [6] years; 455 male [82%]) included in the proteomics assessment, 272 (48.7%) received pitavastatin and 286 (51.3%) received placebo. After adjusting for false discovery rates, pitavastatin increased abundance of procollagen C-endopeptidase enhancer 1 (PCOLCE), neuropilin 1 (NRP-1), major histocompatibility complex class I polypeptide-related sequence A (MIC-A) and B (MIC-B), and decreased abundance of tissue factor pathway inhibitor (TFPI), tumor necrosis factor ligand superfamily member 10 (TRAIL), angiopoietin-related protein 3 (ANGPTL3), and mannose-binding protein C (MBL2). Among these proteins, the association of pitavastatin with PCOLCE (a rate-limiting enzyme of collagen deposition) was greatest, with an effect size of 24.3% (95% CI, 18.0%-30.8%; P < .001). In a transcriptomic analysis, individual collagen genes and collagen gene sets showed increased expression. Among the 195 individuals with plaque at baseline (88 [45.1%] taking pitavastatin, 107 [54.9%] taking placebo), changes in NCP volume were most strongly associated with changes in PCOLCE (%change NCP volume/log2-fold change = -31.9%; 95% CI, -42.9% to -18.7%; P < .001), independent of changes in LDL-C level. Increases in PCOLCE related most strongly to change in the fibro-fatty (<130 Hounsfield units) component of NCP (%change fibro-fatty volume/log2-fold change = -38.5%; 95% CI, -58.1% to -9.7%; P = .01) with a directionally opposite, although nonsignificant, increase in calcified plaque (%change calcified volume/log2-fold change = 34.4%; 95% CI, -7.9% to 96.2%; P = .12). CONCLUSIONS AND RELEVANCE: Results of this secondary analysis of the REPRIEVE randomized clinical trial suggest that PCOLCE may be associated with the atherosclerotic plaque stabilization effects of statins by promoting collagen deposition in the extracellular matrix transforming vulnerable plaque phenotypes to more stable coronary lesions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02344290.

Humans↗

PubMed1998

Procollagen-positive fibroblasts predominantly express fibrogenic growth factors and their receptors in human encapsulation process against foreign body.

This paper addresses the in situ expression of transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), and their receptors in the encapsulation process against a foreign body, using 20 cases of the titanium miniplate as a model of the foreign body, used clinically to fix a fractured mandible. Fibrous tissue formed during the encapsulation process was composed of scar-like and fibrogenic layers, with the former directly facing the foreign body. By immunohistochemistry using pre-fixed frozen sections, only the fibrogenic layer was characterized by expression of type I procollagen (PC-I). Spindle-shaped mesenchymal cells in the fibrogenic layer expressed TGF-beta isoforms and receptors, PDGF isoforms, and PDGF beta-receptor. In contrast, the scar-like layer had few such cells. In both layers, spindle-shaped cells did not express Ki-67 in their nuclei. Double immunofluorescence microscopy for cell identification revealed that most PC-I-positive fibroblasts expressed both isoforms and receptors of TGF-beta and PDGF in the fibrogenic layer, while in contrast, they were expressed by only a small number of CD68-positive macrophages. These results suggest that in the maintenance stage of the human encapsulation process against a foreign body, both TGF-beta and PDGF function cooperatively via their receptors in the fibrogenic layer, with such stimuli markedly diminished in the scar-like layer.

Adolescent↗

PubMed1997

N-terminal peptide of type III procollagen: a possible predictor of colorectal carcinoma recurrence.

BACKGROUND: The first step of colorectal carcinoma spread depends on the ability of the tumor cells to degrade and invade the extracellular matrix (ECM). The objectives of the current study were to evaluate the serum pattern of laminin, C-terminal peptide of Type I (PIP), and N-terminal peptide of Type III (PIIIP) procollagens, markers of ECM synthesis, in the follow-up of patients after resection for colorectal carcinoma and to evaluate their role in predicting local recurrence or metastases. METHODS: A total of 32 patients who had undergone resection for colorectal carcinoma were followed for a median period of 24 months (range, 6-36 months). Every 3 months, laminin, PIP, and PIIIP were measured in the sera together with the tumor markers carcinoembryonic antigen (CEA), CA 19-9, and tissue plasminogen activator (TPA). Twenty-one patients (Group 1) had no signs of recurrence, whereas the remaining 11 (Group 2) developed hepatic (n = 7) or pulmonary (n = 4) metastases. RESULTS: No variations were observed in either group for laminin, CEA, CA 19-9, or TPA, whereas significant increases in PIP and PIIIP were observed in both groups 3 months after surgery. The increase in PIP and PIIIP at the 3-month follow-up was significantly greater in Group 1 than in Group 2. The difference between values at 3 months and basal values enabled a discrimination between Group 1 and Group 2, with a sensitivity of 36% and 91% and a specificity of 71% and 71% for PIP and PIIIP, respectively. CONCLUSIONS: The authors believe PIIIP is useful as an early prognostic indicator of recurrence in the follow-up of patients who have undergone radical resection for colorectal carcinoma.

Adult↗

PubMed1999

Coexpression of the lysyl oxidase-like gene (LOXL) and the gene encoding type III procollagen in induced liver fibrosis.

We have isolated a mouse lysyl oxidase-like (LOXL) cDNA from a mouse embryo cDNA library and used this cDNA to measure changes in steady state levels of LOXL mRNA during the development of carbon tetrachloride-induced liver fibrosis in adult mice. These results revealed the coincident appearance of increased steady state levels of LOXL mRNA and type III procollagen mRNA early in the development of liver fibrosis. In contrast, steady state levels of lysyl oxidase mRNA increased throughout the onset of hepatic fibrosis and appeared in parallel with the increased steady state levels of pro-alphaI (I) collagen mRNA. These findings suggest that the LOXL protein (possibly an isoform of lysyl oxidase) is involved in the development of lysine-derived cross-links in collagenous substrates. Moreover, the substrate specificity of the LOXL protein may be different to that of lysyl oxidase and this difference may be collagen-type specific.

Animals↗

PubMed1990

Serum concentrations of CA 125 and aminoterminal propeptide of type III procollagen (PIIINP) in patients with endometrial carcinoma.

Serum CA 125 (a marker of coelomic epithelial cells) and aminoterminal propeptide of type III procollagen (PIIINP; an indicator of collagen metabolism) concentrations were measured in 148 patients with endometrial carcinoma. An initial serum concentration of CA 125 was pathologic in 17% of the patients, the frequency of abnormal values being higher (P = 0.0001) in advanced (63%) than in early disease (10%). The serum PIIINP concentration was increased in 35% of the patients and more often (P less than 0.05) so in advanced (63%) than in early disease (31%). Among all the patients, at least one of the tumor markers was increased in 43% of the cases. In early disease 12 of 108 patients contracted recurrent cancer. The accuracy of the pathologic CA 125 (9%) and PIIINP (18%) concentrations in their prediction was poor. In the total material, pathologic CA 125 and PIIINP concentrations appeared simultaneously in 11 patients, of whom eight had poor prognoses. In monitoring of treatment response of 24 patients, regression was accompanied by normal or decreasing CA 125 and PIIINP values. The persistence of pathologic CA 125 and/or PIIINP concentration predicted relapse of the malignancy. In progressive disease, CA 125 and PIIINP concentrations together or separately remained at a pathologic level or increased continuously. In clinically stable endometrial carcinoma, CA 125 gave false-negative results in 71% of the determinations and PIIINP only in 12%. The current results suggest the use of CA 125 and PIIINP, simultaneously, in monitoring the clinical course of advanced endometrial carcinoma.

Adult↗

PubMed2001

Alpha-1-antitrypsin stimulates fibroblast proliferation and procollagen production and activates classical MAP kinase signalling pathways.

Connective tissue formation at sites of tissue repair is regulated by matrix protein synthesis and degradation, which in turn is controlled by the balance between proteases and antiproteases. Recent evidence has suggested that antiproteases may also exert direct effects on cell function, including influencing cell migration and proliferation. The antiprotease, alpha1-antitrypsin, is the major circulating serine protease inhibitor which protects tissues from neutrophil elastase attack. Its deficiency is associated with the destruction of connective tissue in the lung and the development of emphysema, whereas accumulation of mutant alpha1-antitrypsin within hepatocytes often leads to liver fibrosis. In this study, we report that alpha1antitrypsin, at physiologically relevant concentrations, promotes fibroblast proliferation, with maximal stimulatory effects of 118 +/- 2% (n=6, P < 0.02) above media controls for cells exposed to 60 microM. We further show that alpha1antitrypsin also stimulates fibroblast procollagen production, independently of its effects on cell proliferation, with values maximally increased by 34 +/- 3% (n = 6, P < 0.01) above media controls at 30 microM. Finally, mechanistic studies to examine the mechanism by which alpha1-antitrypsin acts, showed that alpha1-antitrypsin induced the rapid activation of p42MAPK and p44MAPK (also known as ERK1/2) and that the specific MEK1 inhibitor PD98059 totally blocked alpha1-antitrypsin's mitogenic effects. These results support the hypothesis that alpha1-antitrypsin may play a role in influencing tissue repair in vivo by directly stimulating fibroblast proliferation and extracellular matrix production via classical mitogen-activated signalling pathways.

Cell Division↗

PubMed1998

Identification of elements in the promoter region of the alpha1(I) procollagen gene involved in its up-regulated expression in systemic sclerosis.

OBJECTIVE: To identify regulatory elements in the promoter region of the alpha1(I) procollagen gene (COL1A1) involved in the transcriptional activation of this gene in systemic sclerosis (SSc), and to identify the transcription factors interacting with these regulatory elements. METHODS: Dermal fibroblasts from 6 patients with diffuse SSc of recent onset and from 6 healthy individuals were studied. The transcriptional regulation of COL1A1 was examined by transient transfections with deletion constructs containing portions of the COL1A1 promoter. The DNA binding activity of nuclear proteins recognizing the regulatory regions in the COL1A1 promoter was examined by gel mobility shift assays. A procedure was established to allow the quantitative determination of the amount of DNA binding proteins interacting with the COL1A1 promoter, employing DNA binding protein and DNA titration experiments analyzed by gel mobility shift assays. RESULTS: Maximal chloramphenicol acetyltransferase activity was observed with a -174-bp to +42-bp COL1A1 promoter construct in both normal and SSc cells; however, the activity driven by this construct was 70-260% higher in SSc fibroblasts. Most of the transcriptional activity of the COL1A1 promoter was contained in a minimal promoter region encompassing -174 bp to -84 bp. Electrophoretic mobility shift assays performed with oligonucleotides corresponding to the regions spanning -129/-107 bp and -104/-78 bp of the COL1A1 promoter revealed marked increases in the intensities of DNA-protein complexes formed with both oligonucleotides in nuclear extracts prepared from each of the SSc cell lines in comparison with normal fibroblasts. Competition experiments showed that each of these regions contained elements recognized by Sp1 and nuclear factor 1 (NF-1) binding proteins. A quantitative determination of DNA binding activity recognizing the Sp1 binding element within the -129/-107-bp region showed that it was 23.6 nM in SSc fibroblasts compared with 6.9 nM in normal fibroblasts. CONCLUSION: The results demonstrate that a short region in the proximal promoter of COL1A1 containing 2 tandem NF-1/Sp1 elements displays up-regulated transcriptional activity in SSc fibroblasts, and that SSc fibroblasts contain 3.4-fold greater DNA binding activity recognizing these elements than normal cells.

Binding, Competitive↗

PubMed1983

Increased serum procollagen III aminoterminal peptide in myelofibrosis.

Myelofibrosis has been shown to involve an increase in type III collagen in the marrow. The aminoterminal procollagen III (PC III) peptide fragment is released during the production of PC III by fibroblasts and its serum level is therefore a marker for type III collagen synthesis. Using a recently developed sensitive radioimmunoassay, serum levels of PC III peptide were measured in 30 patients with myeloproliferative disease and 23 normal volunteers. Levels were found to be elevated above normal values in patients with polycythemia vera, even more elevated in patients with polycythemia and evidence of secondary myelofibrosis with myeloid metaplasia, and most strikingly elevated in patients with agnogenic myeloid metaplasia and severe marrow fibrosis. There was a significant association between serum levels of PC III peptide and the extent of reticulin fibrosis in bone marrow biopsies. Serum PC III level appears to be a quantitative marker for myelofibrosis.

Adult↗

PubMed1987

Serum type III procollagen peptide: indicator for pulmonary fibrosis: II. Application in 80 asbestos insulation workers.

An assay for type III procollagen peptide (P-III-P) was applied to serum from 80 asbestos insulation workers in order to evaluate its relationship with pulmonary and pleural fibrosis. The serum peptide levels of 16 control workers were 7.8 +/- 2.0 ng/ml (mean +/- SD). An association between the serum values of P-III-P and the profusion of small irregular opacities on chest X-rays was noted. The levels in the group with moderate interstitial pulmonary fibrosis [profusion category 2(2/1, 2/2, and 2/3)] and with marked interstitial pulmonary fibrosis [profusion category 3(3/3)] were 9.9 +/- 2.3 ng/ml (n = 5) and thus tended to be higher than those of 16 control workers (p less than 0.1). On the other hand, there was not correlation between serum peptide levels and pleural lesions nor between the former and duration of asbestos exposure. From the results of the investigation [part I of which is reported elsewhere (Okazaki et al, 1986)] this assay may be useful for detecting individuals with a more marked tendency for progression of interstitial pulmonary fibrosis due to asbestos exposure in insulation work.

Adult↗

PubMed1989

Lack of association between scleroderma and types I and III procollagen gene restriction fragment length polymorphisms.

Restriction fragment length polymorphisms (RFLPs) in types I and III procollagen genes were studied in 62 scleroderma patients and 138 healthy controls. Allelic frequencies were determined for each RFLP, and comparisons were made between the 2 populations, stratifying them by race when appropriate. No statistically significant differences were observed for the frequencies of any of the RFLPs studied.

Alleles↗

PubMed1985

Collagen synthesis regulation by the aminopropeptide of procollagen I in normal and scleroderma fibroblasts.

The effect of the aminopropeptide of type I procollagen, Col 1(I), on collagen synthesis by normal and scleroderma fibroblasts was investigated. Collagen synthesis was inhibited by about 42% when normal fibroblasts were labeled with 3H-proline in the presence of 4 microM Col 1(I). In contrast, collagen synthesis by scleroderma fibroblasts was inhibited to a lesser degree, about 19%. Furthermore, scleroderma fibroblasts with elevated rates of collagen synthesis (2.5-5 times normal) were inhibited by only about 10%. The data suggest that the increased accumulation of collagen in the skin of scleroderma patients may be related to a defect in the regulation of collagen synthesis by the aminopropeptide.

Adult↗

PubMed1986

Serum amino-terminal type III procollagen peptide in rheumatoid arthritis. Relationship to disease activity, treatment, and development of joint erosions.

Using 2 radioimmunoassays, increased serum levels of amino-terminal type III procollagen peptide and its degradation products were demonstrated in rheumatoid arthritis patients. Patients with active disease showed higher serum propeptide levels than did patients with inactive disease. Unlike D-penicillamine, azathioprine treatment suppressed the propeptide levels in patients with active disease. A 6-month prospective study showed significantly higher initial serum propeptide levels in patients with erosive progression. The propeptide level reflects disease activity and may be a valuable prognostic marker in rheumatoid arthritis.

Adult↗

PubMed1986

Inhibition of excessive scleroderma fibroblast collagen production by recombinant gamma-interferon. Association with a coordinate decrease in types I and III procollagen messenger RNA levels.

The effects of recombinant gamma-interferon (rec gamma-IFN) on collagen production by confluent monolayer cultures of progressive systemic sclerosis (PSS) dermal fibroblasts were studied. Five cell lines obtained from patients with rapidly progressive disease of recent onset were examined. All PSS fibroblast cell lines exhibited increased collagen production when compared with normal skin cell lines. It was found that rec gamma-IFN caused potent inhibition of PSS fibroblast collagen production in a concentration-dependent manner. Greater than 50% inhibition was observed with as little as 50 antiviral units/ml, and maximal effects were attained at a concentration of 500 units/ml. The rec gamma-IFN caused reproducible inhibition of collagen production by the 5 PSS fibroblast cell lines, ranging from 58.9% to 85.6% of control values. Measurement of type I and type III procollagen messenger RNA (mRNA) levels with specific complementary DNA probes demonstrated a coordinate reduction of greater than 60% in mRNA for both transcripts in rec gamma-IFN-treated cells, compared with control cells. These findings indicate that rec gamma-IFN can modulate the excessive collagen biosynthesis characteristic of PSS fibroblasts and that this effect can be explained largely by the gamma-IFN-mediated decrease in specific collagen mRNAs.

Adult↗

PubMed1993

Early-onset osteoarthritis linked to the type II procollagen gene. Detailed clinical phenotype and further analyses of the gene.

OBJECTIVE: To specify in detail the clinical phenotype in 2 Finnish families demonstrating linkage between the type II procollagen gene (COL2A1) and osteoarthritis (OA). We also reevaluated the linkage and screened the exon sequences of the COL2A1 gene for mutations. METHODS: We used single-stranded conformation polymorphism and denaturing gradient-gel electrophoresis techniques for the analyses. RESULTS: The patients' phenotype represented typical, but early-onset, OA. There was no clinical or radiographic evidence of chondrodysplasia. No mutation in the protein-coding regions of the COL2A1 gene could be identified. However, the linkage analysis with a new multiallelic marker resulted in a statistically more significant logarithm of odds (LOD) score than has been reported. CONCLUSION: Familial OA with classic clinical and radiographic findings is tightly linked to the COL2A1 gene. Systematic screening of the 54 exons did not, however, reveal any mutations; this suggests that the mutation may lie in the promoter region or within the introns of this 35-kb gene.

Adolescent↗

PubMed1994

Clinical correlations of osteoarthritis associated with a single-base mutation (arginine519 to cysteine) in type II procollagen gene. A newly defined pathogenesis.

OBJECTIVE: To investigate the occurrence and clinical correlation of the arg519-to-cys mutation in the type II procollagen gene in patients with osteoarthritis (OA). METHODS: Sixty-six subjects from 7 families with a strong family history of generalized OA and 13 patients with erosive OA were evaluated clinically and radiologically. Blood samples from 58 subjects in the familial OA group and from all 13 patients with erosive OA were obtained for DNA analysis. Exon 31 of COL2A1, which spans residue 519, was amplified by polymerase chain reaction. RESULTS: The arg519-to-cys mutation was detected in 2 of the 7 families with generalized OA. In these 2 families, the mutation was present in the 2 probands and in 19 other clinically affected family members, as well as in 3 (so-far) clinically unaffected family members (ages 25, 14, and 11 years). It was absent in 18 clinically unaffected members tested. The mutation was associated with a distinctive pattern of early-onset, aggressive, generalized OA with a mild spinal chondrodysplasia. Inheritance was autosomal dominant. No mutation was found in any of the patients with erosive OA. CONCLUSION: The arg519-to-cys mutation defines a new pathogenic factor in generalized OA with characteristic clinical and radiologic features. The demonstration of a mutation in 3 of 8 families with OA studied thus far suggests a significant incidence of genetically related clinical OA.

Adolescent↗

PubMed1994

Familial spondyloepiphyseal dysplasia tarda, brachydactyly, and precocious osteoarthritis associated with an arginine 75-->cysteine mutation in the procollagen type II gene in a kindred of Chiloe Islanders. I. Clinical, radiographic, and pathologic findings.

OBJECTIVE: To characterize a kindred of Chiloe Islanders with spondyloepiphyseal dysplasia tarda (SEDT), brachydactyly, precocious osteoarthritis (OA), and intraarticular calcification. METHODS: Sixteen family members underwent a complete physical examination, anthropometric measurements, radiographic studies of the spine and peripheral joints, and analysis of the type II procollagen gene (COL2A1). RESULTS: Seven family members presented with SEDT, brachydactyly, precocious OA, and periarticular calcification while 2 others had the same syndrome but without brachydactyly. The inheritance was autosomal dominant, and the disease cosegregated with a base substitution in the COL2A1 gene. CONCLUSION: The syndrome o SEDT, precocious OA, and brachydactyly in a kindred of Chiloe Islanders is associated with a point mutation in 1 allele of the COL2A1 gene. The relationship of this type of SEDT to familial calcium pyrophosphate dihydrate deposition disease and idiopathic hip dysplasia, both endemic in Chiloe Islanders, needs to be further investigated.

Adult↗

PubMed1978

Localization of antigenic activity and immunogenic capacity in different conformational domains of procollagen peptide.

The antibody response to the amino-terminal CNBr peptide of sheep procollagen which consists of a globular and a collagenous segment, was studied in inbred strains of mice. The determinants reacting with antibody could be localized in the globular domain and were lost by reduction of disulfide bridges. The ability to induce an antibody response required the collagen-like sequences and was independent of the triple-helical conformation of this segment. The data were interpreted as indicating a different conformation dependence of hapten and carrier determinants.

Animals↗

PubMed1999

Transforming growth factor beta1 induces the expression of alpha1(I) procollagen mRNA by a hydrogen peroxide-C/EBPbeta-dependent mechanism in rat hepatic stellate cells.

Oxidative stress plays a key role in liver fibrosis. Both inflammatory cells and activated Kupffer cells produce H2O2, an oxidant involved in the activation of hepatic stellate cells (HSC). Increased production of reactive oxygen intermediates (ROIs) in fibrotic livers is associated in part with the up-regulation of transforming growth factor beta (TGF-beta), and this cytokine enhances collagen production by cultured HSC. However, the possible link between oxidative stress and the molecular mechanisms by which TGF-beta induces collagen gene expression in HSC remains to be elucidated. To address this question, we investigated whether H2O2 is a mediator of TGF-beta-elicited alpha1(I) collagen gene (col1a1) up-regulation. We demonstrated that TGF-beta induces the accumulation of H2O2, and that this oxidant is, in turn, directly involved in up-regulating the expression of the col1a1 gene. While the addition of H2O2 to HSC induced the expression of alpha1(I) procollagen mRNA, catalase, an H2O2 enzyme scavenger, abrogated TGF-beta-mediated col1a1 gene up-regulation. We transfected HSC with chimeric plasmids driven by different segments of the mouse col1a1 promoter and mapped a cis-acting element (-370 to -344) essential for TGF-beta responsiveness. We further showed that TGF-beta induced the activation and binding of a C/EBPbeta-containing transcriptional complex to this sequence, an effect that was also mimicked by the addition of H2O2. Taken together, these data demonstrate a direct connection between TGF-beta-mediated accumulation of H2O2 and the up-regulation of col1a1 gene in HSC.

Animals↗