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JACC. Heart Failure Jan 2023Myocardial fibrosis may increase vulnerability to poor prognosis in patients with heart failure (HF), even in those patients exhibiting left ventricular reverse... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Myocardial fibrosis may increase vulnerability to poor prognosis in patients with heart failure (HF), even in those patients exhibiting left ventricular reverse remodeling (LVRR) after guideline-based therapies.
OBJECTIVES
This study sought to characterize fibrosis at baseline in patients with HF with left ventricular ejection fraction (LVEF) <50% by determining serum collagen type I-derived peptides (procollagen type I C-terminal propeptide [PICP] and ratio of collagen type I C-terminal telopeptide to matrix metalloproteinase-1) and to evaluate their association with LVRR and prognosis.
METHODS
Peptides were determined in 1,034 patients with HF at baseline. One-year echocardiography was available in 665 patients. Associations of peptides with 1-year changes in echocardiographic variables were analyzed by multivariable linear mixed models. LVEF was considered improved if it increased by ≥15% or to ≥50% or if it increased by ≥10% to >40% in patients with LVEF ≤40%. Cardiovascular death and HF-related outcomes were analyzed in all patients randomized to derivation (n = 648) and validation (n = 386) cohorts.
RESULTS
Continuous associations with echocardiographic changes were observed only for PICP. Compared with high-PICP (≥108.1 ng/mL) patients, low-PICP (<108.1 ng/mL) patients exhibited enhanced LVRR and a lower risk of HF-related outcomes (P ≤ 0.018), with women and nonischemic patients with HF showing a stronger LVEF increase (interaction P ≤ 0.010). LVEF increase was associated with a better prognosis, particularly in low-PICP patients (interaction P ≤ 0.029). Only patients with both low PICP and improved LVEF exhibited a better clinical evolution than patients with nonimproved LVEF (P < 0.001).
CONCLUSIONS
Phenotyping with PICP, a peptide associated with myocardial fibrosis, may be useful to differentiate patients with HF who are more likely to experience clinical myocardial recovery from those with partial myocardial improvement.
Topics: Humans; Female; Collagen Type I; Stroke Volume; Heart Failure; Ventricular Function, Left; Peptide Fragments; Procollagen; Biomarkers; Collagen; Peptides; Cardiomyopathies; Fibrosis
PubMed: 36599551
DOI: 10.1016/j.jchf.2022.09.008 -
Biochimica Et Biophysica Acta.... Sep 2019Mutations in the type I procollagen C-propeptide occur in ~6.5% of Osteogenesis Imperfecta (OI) patients. They are of special interest because this region of procollagen...
Mutations in the type I procollagen C-propeptide occur in ~6.5% of Osteogenesis Imperfecta (OI) patients. They are of special interest because this region of procollagen is involved in α chain selection and folding, but is processed prior to fibril assembly and is absent in mature collagen fibrils in tissue. We investigated the consequences of seven COL1A1 C-propeptide mutations for collagen biochemistry in comparison to three probands with classical glycine substitutions in the collagen helix near the C-propeptide and a normal control. Procollagens with C-propeptide defects showed the expected delayed chain incorporation, slow folding and overmodification. Immunofluorescence microscopy indicated that procollagen with C-propeptide defects was mislocalized to the ER lumen, in contrast to the ER membrane localization of normal procollagen and procollagen with helical substitutions. Notably, pericellular processing of procollagen with C-propeptide mutations was defective, with accumulation of pC-collagen and/or reduced production of mature collagen. In vitro cleavage assays with BMP-1 ± PCPE-1 confirmed impaired C-propeptide processing of procollagens containing mutant proα1(I) chains. Overmodified collagens were incorporated into the matrix in culture. Dermal fibrils showed alterations in average diameter and diameter variability and bone fibrils were disorganized. Altered ER-localization and reduced pericellular processing of defective C-propeptides are expected to contribute to abnormal osteoblast differentiation and matrix function, respectively.
Topics: Calorimetry, Differential Scanning; Cells, Cultured; Collagen Type I; Collagen Type I, alpha 1 Chain; Endoplasmic Reticulum; Fibroblasts; Humans; Microscopy, Fluorescence; Mutation, Missense; Osteogenesis Imperfecta; Procollagen; Protein Structure, Tertiary
PubMed: 31055083
DOI: 10.1016/j.bbadis.2019.04.018 -
Proceedings of the National Academy of... Jan 2024Newly synthesized secretory proteins are exported from the endoplasmic reticulum (ER) at specialized subcompartments called exit sites (ERES). Cargoes like procollagen...
Newly synthesized secretory proteins are exported from the endoplasmic reticulum (ER) at specialized subcompartments called exit sites (ERES). Cargoes like procollagen are too large for export by the standard COPII-coated vesicle of 60 nm average diameter. We have previously suggested that procollagen is transported from the ER to the next secretory organelle, the ER-Golgi intermediate compartment (ERGIC), in TANGO1-dependent interorganelle tunnels. In the theoretical model presented here, we suggest that intrinsically disordered domains of TANGO1 in the ER lumen induce an entropic contraction, which exerts a force that draws procollagen toward the ERES. Within this framework, molecular gradients of pH and/or HSP47 between the ER and ERGIC create a force in the order of tens of femto-Newtons. This force is substantial enough to propel procollagen from the ER at a speed of approximately 1 nm · s. This calculated speed and the quantities of collagen secreted are similar to its observed physiological secretion rate in fibroblasts, consistent with the proposal that ER export is the rate-limiting step for procollagen secretion. Hence, the mechanism we propose is theoretically adequate to explain how cells can utilize molecular gradients and export procollagens at a rate commensurate with physiological needs.
Topics: Procollagen; Protein Transport; Collagen; Biological Transport; Endoplasmic Reticulum; Golgi Apparatus; COP-Coated Vesicles
PubMed: 38147551
DOI: 10.1073/pnas.2310404120 -
Calcified Tissue International Dec 2022Determinants of low bone turnover in type 2 diabetes (T2DM) are poorly understood. To investigate the relationship between markers of bone turnover, glycaemic control,... (Observational Study)
Observational Study
Determinants of low bone turnover in type 2 diabetes (T2DM) are poorly understood. To investigate the relationship between markers of bone turnover, glycaemic control, disease duration and calciotropic hormones in T2DM we assessed baseline biochemical data from the DiabOS Study, a prospective multicenter observational cohort study. In a cross-sectional study-design data from 110 postmenopausal women and men aged 50-75 years diagnosed with T2DM for at least 3 years and 92 non-diabetic controls were evaluated. Biochemical markers of bone formation (N-terminal propeptide of type I procollagen [PINP]), bone-specific alkaline phosphatase [BAP]) and resorption (C-terminal cross-linking telopeptide of type I collagen [CTX]), measures of calcium homeostasis (intact parathormone [iPTH], 25-Hydroxyvitamin D, calcium, magnesium) and glycaemic control were assessed. After adjustment for age, gender and body mass index (BMI), patients with T2DM had lower serum levels of PINP (p < 0.001), CTX (p < 0.001), iPTH (p = 0.03) and magnesium (p < 0.001) compared to controls. Serum calcium, creatinine, 25-Hydroxyvitamin D and sclerostin did not differ between both groups. In multivariate linear regression analyses only serum iPTH remained an independent determinant of bone turnover markers in T2DM (PINP: p = 0.02; CTX: p < 0.001 and BAP: p < 0.01), whereas glycated haemoglobin (HbA1c), disease duration, age and BMI were not associated with bone turnover. In conclusion low bone turnover in T2DM is associated with low iPTH. The underlying mechanism remains to be elucidated.
Topics: Male; Humans; Female; Diabetes Mellitus, Type 2; Calcium; Cross-Sectional Studies; Magnesium; Prospective Studies; Bone Remodeling; Collagen Type I; Biomarkers; Parathyroid Hormone; Alkaline Phosphatase; Procollagen; Bone Density
PubMed: 36190530
DOI: 10.1007/s00223-022-01022-7 -
Calcified Tissue International Feb 2023Bone turnover markers (BTMs) have been developed many years ago to study, in combination with imaging techniques, bone remodeling in adults. In children and adolescents,... (Review)
Review
Bone turnover markers (BTMs) have been developed many years ago to study, in combination with imaging techniques, bone remodeling in adults. In children and adolescents, bone metabolism differs from adults since it implies both growth and bone remodeling, suggesting an age- and gender-dependent BTM concentration. Therefore, specific studies have evaluated BTMs in not only physiological but also pathological conditions. However, in pediatrics, the use of BTMs in clinical practice is still limited due to these many children-related specificities. This review will discuss about physiological levels of BTMs as well as their modifications under pathological conditions in children and adolescents. A focus is also given on analytical and clinical challenges that restrain BTM usefulness in pediatrics.
Topics: Adult; Humans; Child; Adolescent; Bone Remodeling; Biomarkers; Collagen Type I; Procollagen; Reference Values; Bone Density
PubMed: 35243530
DOI: 10.1007/s00223-022-00964-2 -
Proceedings of the National Academy of... Oct 2018Type I collagen is the main component of bone matrix and other connective tissues. Rerouting of its procollagen precursor to a degradative pathway is crucial for...
Type I collagen is the main component of bone matrix and other connective tissues. Rerouting of its procollagen precursor to a degradative pathway is crucial for osteoblast survival in pathologies involving excessive intracellular buildup of procollagen that is improperly folded and/or trafficked. What cellular mechanisms underlie this rerouting remains unclear. To study these mechanisms, we employed live-cell imaging and correlative light and electron microscopy (CLEM) to examine procollagen trafficking both in wild-type mouse osteoblasts and osteoblasts expressing a bone pathology-causing mutant procollagen. We found that although most procollagen molecules successfully trafficked through the secretory pathway in these cells, a subpopulation did not. The latter molecules appeared in numerous dispersed puncta colocalizing with COPII subunits, autophagy markers and ubiquitin machinery, with more puncta seen in mutant procollagen-expressing cells. Blocking endoplasmic reticulum exit site (ERES) formation suppressed the number of these puncta, suggesting they formed after procollagen entry into ERESs. The punctate structures containing procollagen, COPII, and autophagic markers did not move toward the Golgi but instead were relatively immobile. They appeared to be quickly engulfed by nearby lysosomes through a bafilomycin-insensitive pathway. CLEM and fluorescence recovery after photobleaching experiments suggested engulfment occurred through a noncanonical form of autophagy resembling microautophagy of ERESs. Overall, our findings reveal that a subset of procollagen molecules is directed toward lysosomal degradation through an autophagic pathway originating at ERESs, providing a mechanism to remove excess procollagen from cells.
Topics: 3T3 Cells; Animals; Autophagy; Cell Line; Collagen Type I; Endoplasmic Reticulum; Golgi Apparatus; Lysosomes; Mice; Osteoblasts; Procollagen; Protein Transport
PubMed: 30287488
DOI: 10.1073/pnas.1814552115 -
Photochemistry and Photobiology Nov 2022Factors promoting fibroblast proliferation and collagen synthesis can subsequently enhance wound healing. This study aimed to assess the effect of 810 and 940 nm diode...
Factors promoting fibroblast proliferation and collagen synthesis can subsequently enhance wound healing. This study aimed to assess the effect of 810 and 940 nm diode laser on fibroblast proliferation and procollagen gene expression. In this study, human gingival fibroblasts were cultured in Dulbecco's modified Eagle's medium and underwent 810 and 940 nm diode laser irradiation once, twice, thrice and four times at 1, 3, 5 and 7 days after culture. The methyl thiazolyl tetrazolium assay was performed to assess the proliferation while the real-time polymerase chain reaction was performed to assess the expression of procollagen gene at the mRNA level. We applied two-way ANOVA and Tukey's test for analysis. Wavelength had no significant effect on the proliferation of gingival fibroblasts, but increasing the number of irradiation sessions of both wavelengths increased the proliferation of human gingival fibroblasts. Significant differences were noted in the number of human gingival fibroblasts between groups irradiated 1 and 4 and also 2 and 4 times. Procollagen gene was well expressed in all groups but its expression was significantly higher in 940 nm laser group after four irradiation cycles. Four times radiation of 940 nm laser seems to be more effective than all others.
Topics: Humans; Lasers, Semiconductor; Procollagen; Gingiva; Fibroblasts; Cell Proliferation; Cells, Cultured
PubMed: 35377467
DOI: 10.1111/php.13630 -
Molecular Biology of the Cell Mar 2022Collagen is the major protein component of the extracellular matrix. Synthesis of procollagens starts in the endoplasmic reticulum (ER), and three α chains form a rigid...
Collagen is the major protein component of the extracellular matrix. Synthesis of procollagens starts in the endoplasmic reticulum (ER), and three α chains form a rigid triple helix 300-400 nm in length. It remains unclear how such a large cargo is transported from the ER to the Golgi apparatus. In this study, to elucidate the intracellular transport of fibril-forming collagens, we fused cysteine-free GFP to the N-telopeptide region of procollagen III (GFP-COL3A1) and analyzed transport by live-cell imaging. We found that the maturation dynamics of procollagen III was largely different from that of network-forming procollagen IV. Proline hydroxylation of procollagen III uniquely triggered the formation of intralumenal droplet-like structures, similarly to events caused by liquid-liquid phase separation, and ER exit sites surrounded large droplets containing chaperones. Procollagen III was transported to the Golgi apparatus via vesicular and tubular carriers containing ERGIC53 and RAB1B; this process required TANGO1 and CUL3, which we previously reported to be dispensable for procollagen IV. GFP-COL3A1 and mCherry-α1AT were cotransported in the same vesicle. Based on these findings, we propose that shortly after ER exit, enlarged carriers containing procollagen III fuse to ERGIC for transport to the Golgi apparatus by conventional cargo carriers.
Topics: Biological Transport; Endoplasmic Reticulum; Golgi Apparatus; Procollagen; Protein Transport
PubMed: 35044867
DOI: 10.1091/mbc.E21-07-0372 -
Structure (London, England : 1993) Oct 2018In this issue of Structure, Pulido et al. (2018) determine the crystal structure of procollagen C-proteinase enhancer-1 (PCPE-1)/procollagen III complex and identify...
In this issue of Structure, Pulido et al. (2018) determine the crystal structure of procollagen C-proteinase enhancer-1 (PCPE-1)/procollagen III complex and identify that PCPE-1 unwinds the stalk of the procollagen III trimer, liberating a single chain to facilitate binding and cleavage by BMP-1 proteinases for subsequent fibrillar collagen assembly.
Topics: Bone Morphogenetic Protein 1; Extracellular Matrix Proteins; Glycoproteins; Procollagen
PubMed: 30282017
DOI: 10.1016/j.str.2018.09.003 -
Taiwanese Journal of Obstetrics &... Jan 2022To evaluate the association between P1NP and bone strength in postmenopausal women treated with teriparatide.
OBJECTIVE
To evaluate the association between P1NP and bone strength in postmenopausal women treated with teriparatide.
MATERIALS AND METHODS
This prospective study enrolled 248 postmenopausal women with severe osteoporosis treated with teriparatide. Procollagen type 1 N-terminal propeptide (P1NP) were assessed at baseline, 3, 6, and 12 months. Lumbar spine (LS), femoral neck (FN), and total hip (TH) bone mineral density (BMD) and LS trabecular bone score (TBS) were measured by Dual-energy x-ray absorptiometry at baseline and 12 months.
RESULTS
With teriparatide use, P1NP levels increase and peaked at 6 months. Significant increase in LS and hip BMD and LS TBS were also noted. The percentage change or absolute change >10 μg/L in PINP at 3 months was only related to changes in LS BMD at 12 months. With a median baseline P1NP level was 65.5 ng/mL, we found no correlation between P1NP and LS and hip BMD nor LS TBS. There was no association between LS TBS and axial BMD. After treatment, there was also no significance between the changes in TBS and axial BMD. Over the study period, 83.9% of the 248 participants were persistent with teriparatide at 3 months, 77.8% at 6 months, and 67.3% women at 12 months.
CONCLUSION
P1NP levels may provide a signal of osteoporosis risk but is not related to bone strength. Early changes in P1NP may offer information regarding subsequent BMD response so standardized monitoring of P1NP levels at baseline and at 3 months should be considered during osteoporosis therapy. As an additional benefit, serum level monitoring during treatment may also improve medication persistence.
Topics: Absorptiometry, Photon; Aged; Aged, 80 and over; Bone Density; Bone Density Conservation Agents; Female; Humans; Osteoporosis, Postmenopausal; Peptide Fragments; Postmenopause; Procollagen; Prospective Studies; Teriparatide
PubMed: 35181054
DOI: 10.1016/j.tjog.2021.11.017