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Biomechanics and Modeling in... Feb 2020Deposition of elastin and collagen in the aorta correlates with increases in blood pressure and flow during development, suggesting that the aorta adjusts its mechanical...
Deposition of elastin and collagen in the aorta correlates with increases in blood pressure and flow during development, suggesting that the aorta adjusts its mechanical properties in response to hemodynamic stresses. Elastin knockout (Eln) mice have high blood pressure and pathological remodeling of the aorta and die soon after birth. We hypothesized that decreasing blood pressure in Eln mice during development may reduce hemodynamic stresses and alleviate pathological remodeling of the aorta. We treated Eln and Eln mice with the anti-hypertensive medication captopril throughout embryonic development and then evaluated left ventricular (LV) pressure and aortic remodeling at birth. We found that captopril treatment decreased Eln LV pressure to values near Eln mice and alleviated the wall thickening and changes in mechanical behavior observed in untreated Eln aorta. The changes in thickness and mechanical behavior in captopril-treated Eln aorta were not due to alterations in measured elastin or collagen amounts, but may have been caused by alterations in smooth muscle cell (SMC) properties. We used a constitutive model to understand how changes in stress contributions of each wall component could explain the observed changes in composite mechanical behavior. Our modeling results show that alterations in the collagen natural configuration and SMC properties in the absence of elastin may explain untreated Eln aortic behavior and that partial rescue of the SMC properties may account for captopril-treated Eln aortic behavior.
Topics: Animals; Animals, Newborn; Aorta; Biomechanical Phenomena; Blood Pressure; Captopril; Desmosine; Elastin; Extracellular Matrix Proteins; Gene Expression Regulation; Heart Rate; Heart Ventricles; Hydroxyproline; Mice, Knockout; Myocytes, Smooth Muscle; RNA, Messenger; Receptors, Angiotensin; Stress, Mechanical; Vascular Remodeling
PubMed: 31270728
DOI: 10.1007/s10237-019-01198-2 -
Matrix Biology : Journal of the... Sep 2014This study aimed to characterize the structures of two elastin-like constructs, one composed of a cross-linked elastin-like polypeptide and the other one of cross-linked...
This study aimed to characterize the structures of two elastin-like constructs, one composed of a cross-linked elastin-like polypeptide and the other one of cross-linked tropoelastin, and native aortic elastin. The structures of the insoluble materials and human aortic elastin were investigated using scanning electron microscopy. Additionally, all samples were digested with enzymes of different specificities, and the resultant peptide mixtures were characterized by ESI mass spectrometry and MALDI mass spectrometry. The MS(2) data was used to sequence linear peptides, and cross-linked species were analyzed with the recently developed software PolyLinX. This enabled the identification of two intramolecularly cross-linked peptides containing allysine aldols in the two constructs. The presence of the tetrafunctional cross-link desmosine was shown for all analyzed materials and its quantification revealed that the cross-linking degree of the two in vitro cross-linked materials was significantly lower than that of native elastin. Molecular dynamics simulations were performed, based on molecular species identified in the samples, to follow the formation of elastin cross-links. The results provide evidence for the significance of the GVGTP hinge region of domain 23 for the formation of elastin cross-links. Overall, this work provides important insight into structural similarities and differences between elastin-like constructs and native elastin. Furthermore, it represents a step toward the elucidation of the complex cross-linking pattern of mature elastin.
Topics: Amino Acid Sequence; Aorta; Cross-Linking Reagents; Elastin; Humans; Microscopy, Electron, Scanning; Models, Molecular; Molecular Conformation; Molecular Dynamics Simulation; Molecular Sequence Data; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 25068896
DOI: 10.1016/j.matbio.2014.07.006 -
International Journal of Chronic... 2022Several mechanisms have been proposed to explain why chronic obstructive pulmonary disease (COPD) impairs the prognosis of coronary events. We aimed to explore COPD...
Impact of Spirometrically Confirmed Chronic Obstructive Pulmonary Disease on Arterial Stiffness and Surfactant Protein D After Percutaneous Coronary Intervention. The CATEPOC Study.
BACKGROUND
Several mechanisms have been proposed to explain why chronic obstructive pulmonary disease (COPD) impairs the prognosis of coronary events. We aimed to explore COPD variables related to a worse prognosis in patients undergoing percutaneous coronary intervention (PCI).
METHODS
Patients with an acute coronary event treated by PCI were prospectively included. One month after discharge, clinical characteristics, comorbidities measured with the Charlson index, and prognostic coronary scales (logistic EuroSCORE; GRACE 2.0) were collected. Post-bronchodilator spirometry, arterial stiffness, and serum inflammatory and myocardial biomarkers were measured. Lung plasmatic biomarkers (Surfactant protein D, desmosine, and Clara cell secretory protein-16) were determined with ELISA. COPD was defined by the fixed ratio (FEV1/FVC <70%). Spirometric values were also analyzed as continuous variables using adjusted and non-adjusted ANCOVA analysis. Finally, we evaluated the presence of a respiratory pattern defined by non-stratified spirometric values and pulmonary biomarkers.
RESULTS
A total of 164 patients with a mean age of 65 (±10) years (79% males) were included. COPD was diagnosed in 56 (34%) patients (68% previously undiagnosed). COPD patients had a longer smoking history, higher scores on the EuroSCORE (p < 0.0001) and GRACE 2.0 (p < 0.001) scales, and more comorbidities (p = 0.006). Arterial stiffness determined by pulse wave velocity was increased in COPD patients (7.35 m/s vs 6.60 m/s; p = 0.006). Serum values of high sensitive T troponin (p = 0.007) and surfactant protein D (p = 0.003) were also higher in COPD patients. FEV1% remained significantly associated with arterial stiffness and surfactant protein D in the adjusted ANCOVA analysis. In the cluster exploration, 53% of the patients had a respiratory pattern.
CONCLUSION
COPD affects one-third of patients with an acute coronary event and frequently remains undiagnosed. Several mechanisms, including arterial stiffness and SPD, were increased in COPD patients. Their relationship with the prognosis should be confirmed with longitudinal follow-up of the cohort.
Topics: Aged; Female; Humans; Male; Biomarkers; Bronchodilator Agents; Desmosine; Percutaneous Coronary Intervention; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Pulse Wave Analysis; Troponin; Uteroglobin; Vascular Stiffness; Middle Aged
PubMed: 36267326
DOI: 10.2147/COPD.S373853 -
Microbiology (Reading, England) Jul 2015Previous studies have demonstrated that Pseudomonas aeruginosa PAO1 is chemotactic towards proteinogenic amino acids, however, the chemotaxis response of this strain...
Previous studies have demonstrated that Pseudomonas aeruginosa PAO1 is chemotactic towards proteinogenic amino acids, however, the chemotaxis response of this strain towards non-proteinogenic amino acids and the specific chemoreceptors involved in this response are essentially unknown. In this study, we analysed the chemotactic response of PAO1 towards two degradation products of elastin, the lysine-rich, non-proteinogenic amino acids, desmosine and isodesmosine. We observed that isodesmosine, a potential biomarker for different diseases, served as a chemoattractant for PAO1. A screen of 251methyl-accepting chemotaxis proteins mutants of PAO1 identified PctA as the chemoreceptor for isodesmosine. We also showed that the positive chemotactic response to isodesmosine is potentially common by demonstrating chemoattraction in 12 of 15 diverse (in terms of source of isolation) clinical isolates, suggesting that the chemotactic response to this non-proteinogenic amino acid might be a conserved feature of acute infection isolates and thus could influence the colonization of potential infection sites.
Topics: Bacterial Proteins; Chemotactic Factors; Chemotaxis; Desmosine; Elastin; Humans; Isodesmosine; Pseudomonas Infections; Pseudomonas aeruginosa
PubMed: 25855762
DOI: 10.1099/mic.0.000090 -
Investigative Ophthalmology & Visual... Jan 2016Current literature contains scant information regarding the extent of enzymatic collagen cross-linking in the keratoconus (KC) cornea. The aim of the present study was...
PURPOSE
Current literature contains scant information regarding the extent of enzymatic collagen cross-linking in the keratoconus (KC) cornea. The aim of the present study was to examine levels of enzymatic lysyl oxidase-derived cross-links in stromal collagen in KC tissue, and to correlate the cross-link levels with collagen fibril stability as determined by thermal denaturation temperature (Tm).
METHODS
Surgical KC samples (n = 17) and Eye-Bank control (n = 11) corneas of age 18 to 68 years were analyzed. The samples were defatted, reduced (NaBH4), hydrolyzed (6N HCl at 110°C for 18 hours), and cellulose enriched before analysis by C8 high-performance liquid chromatography equipped with parallel fluorescent and mass detectors in selective ion monitoring mode (20 mM heptafluorobutyric acid/methanol 70:30 isocratic at 1 mL/min). Nine different cross-links were measured, and the cross-link density was determined relative to collagen content (determined colorimetrically). The Tm was determined by differential scanning calorimetry.
RESULTS
Cross-links detected were dihydroxylysinonorleucine (DHLNL), hydroxylysinonorleucine, lysinonorleucine (LNL), and histidinohydroxylysinonorleucine in both control and KC samples. Higher DHLNL levels were detected in KC, whereas the dominant cross-link, LNL, was decreased in KC samples. Decreased LNL levels were observed among KC ≤ 40 corneas. There was no difference in total cross-link density between KC samples and the controls. Pyridinolines, desmosines, and pentosidine were not detected. There was no notable correlation between cross-link levels with fibril instability as determined by Tm.
CONCLUSIONS
Lower levels of LNL in the KC cornea suggest that there might be a cross-linking defect either in fibrillar collagen or the microfibrillar elastic network composed of fibrillin.
Topics: Adolescent; Adult; Aged; Chromatography, High Pressure Liquid; Cornea; Humans; Keratoconus; Mass Spectrometry; Middle Aged; Protein-Lysine 6-Oxidase; Young Adult
PubMed: 26780316
DOI: 10.1167/iovs.15-18105 -
Biophysical Journal Apr 2015Elastin, the principal component of the elastic fiber of the extracellular matrix, imparts to vertebrate tissues remarkable resilience and longevity. This work focuses...
Elastin, the principal component of the elastic fiber of the extracellular matrix, imparts to vertebrate tissues remarkable resilience and longevity. This work focuses on elucidating dynamical and structural modifications of porcine aortic elastin exposed to glucose by solid-state NMR spectroscopic and relaxation methodologies. Results from macroscopic stress-strain tests are also presented and indicate that glucose-treated elastin is mechanically stiffer than the same tissue without glucose treatment. These measurements show a large hysteresis in the stress-strain behavior of glucose-treated elastin-a well-known signature of viscoelasticity. Two-dimensional relaxation NMR methods were used to investigate the correlation time, distribution, and population of water in these samples. Differences are observed between the relative populations of water, whereas the measured correlation times of tumbling motion of water across the samples were similar. (13)C magic-angle-spinning NMR methods were applied to investigate structural and dynamical modifications after glucose treatment. Although some overall structure is preserved, the process of glucose exposure results in more heterogeneous structures and slower mobility. The correlation times of tumbling motion of the (13)C-(1)H internuclear vectors in the glucose-treated sample are larger than in untreated samples, pointing to their more rigid structure. The (13)C cross-polarization spectra reveal a notably increased α-helical character in the alanine motifs after glucose exposure. Results from molecular dynamics simulations are provided that add further insight into dynamical and structural changes of a short repeat, [VPGVG]5, an alanine pentamer, desmosine, and isodesmosine sites with and without glucose. The simulations point to changes in the entropic and energetic contributions in the retractive forces of VPGVG and AAAAA motifs. The most notable change is the increase of the energetic contribution in the retractive force due to peptide-glucose interactions of the VPGVG motif, which may play an important role in the observed stiffening in glucose-treated elastin.
Topics: Amino Acid Motifs; Animals; Aorta; Elasticity; Elastin; Glucose; Molecular Dynamics Simulation; Protein Binding; Protein Structure, Tertiary; Swine; Viscosity
PubMed: 25863067
DOI: 10.1016/j.bpj.2015.02.005 -
International Journal of Chronic... 2017A novel therapy for COPD involving the use of aerosolized hyaluronan (HA) was tested on a small cohort of COPD patients to determine both its safety and efficacy in... (Randomized Controlled Trial)
Randomized Controlled Trial
A novel therapy for COPD involving the use of aerosolized hyaluronan (HA) was tested on a small cohort of COPD patients to determine both its safety and efficacy in reducing levels of desmosine and isodesmosine (DID), biomarkers for elastin degradation. In a 2-week, randomized, double-blind trial, 8 patients receiving 150 kDa HA (mean molecular weight) and 3 others given placebo did not show significant adverse effects with regard to spirometry, electrocardiograms, and hematological indices. Furthermore, measurements of DID in plasma from HA-treated patients indicated a progressive decrease over a 3-week period following initiation of treatment (=-0.98; =0.02), whereas patients receiving placebo showed no reduction in DID (=-0.70; =0.30). Measurements of sputum in the HA-treated group also revealed a progressive decrease in DID (=-0.97; =0.03), but this finding was limited by the absence of similar measurements in the placebo group. Nevertheless, the results of this small, pilot study support a longer-term trial of HA in a larger population of COPD patients.
Topics: Administration, Inhalation; Adult; Aerosols; Aged; Arizona; Biomarkers; Desmosine; Double-Blind Method; Elastin; Humans; Hyaluronic Acid; Isodesmosine; Lung; Middle Aged; New York City; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Sputum; Time Factors; Treatment Outcome
PubMed: 29075107
DOI: 10.2147/COPD.S142156 -
Journal of Clinical Medicine Jul 2019Elastin degradation is accelerated in chronic obstructive pulmonary disease (COPD) and is partially regulated by Matrix Gla Protein (MGP), via a vitamin K-dependent...
Elastin degradation is accelerated in chronic obstructive pulmonary disease (COPD) and is partially regulated by Matrix Gla Protein (MGP), via a vitamin K-dependent pathway. The aim was to assess vitamin K status in COPD as well as associations between vitamin K status, elastin degradation, lung function parameters and mortality. A total of 192 COPD patients and 186 age-matched controls were included. In addition to this, 290 COPD patients from a second independent longitudinal cohort were also included. Vitamin K status was assessed by measuring plasma inactive MGP levels and rates of elastin degradation by measuring plasma desmosine levels. Reduced vitamin K status was found in COPD patients compared to smoking controls ( < 0.0005) and controls who had never smoked ( = 0.001). Vitamin K status was inversely associated with desmosine (cohort 1: = 0.001; cohort 2: = 0.004). Only few significant associations between vitamin K status and lung function parameters were found. Mortality was higher in COPD patients within the quartile with the lowest vitamin K status compared to those within the other quartiles (hazard ratio 1.85, 95% confidence interval (CI), 1.21-2.83, = 0.005). In conclusion, we demonstrated reduced vitamin K status in COPD and an inverse association between vitamin K status and elastin degradation rate. Our results therefore suggest a potential role of vitamin K in COPD pathogenesis.
PubMed: 31357639
DOI: 10.3390/jcm8081116 -
Scientific Reports Aug 2017Tendon is composed of fascicles bound together by the interfascicular matrix (IFM). Energy storing tendons are more elastic and extensible than positional tendons;...
Tendon is composed of fascicles bound together by the interfascicular matrix (IFM). Energy storing tendons are more elastic and extensible than positional tendons; behaviour provided by specialisation of the IFM to enable repeated interfascicular sliding and recoil. With ageing, the IFM becomes stiffer and less fatigue resistant, potentially explaining why older tendons become more injury-prone. Recent data indicates enrichment of elastin within the IFM, but this has yet to be quantified. We hypothesised that elastin is more prevalent in energy storing than positional tendons, and is mainly localised to the IFM. Further, we hypothesised that elastin becomes disorganised and fragmented, and decreases in amount with ageing, especially in energy storing tendons. Biochemical analyses and immunohistochemical techniques were used to determine elastin content and organisation, in young and old equine energy storing and positional tendons. Supporting the hypothesis, elastin localises to the IFM of energy storing tendons, reducing in quantity and becoming more disorganised with ageing. These changes may contribute to the increased injury risk in aged energy storing tendons. Full understanding of the processes leading to loss of elastin and its disorganisation with ageing may aid in the development of treatments to prevent age related tendinopathy.
Topics: Aging; Animals; Desmosine; Elastin; Extracellular Matrix; Fascia; Fluorescent Antibody Technique; Horses; Tendinopathy; Tendons
PubMed: 28855560
DOI: 10.1038/s41598-017-09995-4 -
Chronic Obstructive Pulmonary Diseases... Nov 2016The RAPID (NCT00261833; N=180) and RAPID Extension (NCT00670007; N=140) trials demonstrated significantly reduced lung density decline in patients with alpha-1...
The RAPID (NCT00261833; N=180) and RAPID Extension (NCT00670007; N=140) trials demonstrated significantly reduced lung density decline in patients with alpha-1 antitrypsin deficiency (AATD) receiving alpha-1 proteinase inhibitor (A1PI) versus placebo. Desmosine and isodesmosine (DES/IDES) are unique crosslinkers of mature elastin fibers and are utilized as measures of elastin degradation. The aim of this post-hoc study was to determine the effect of A1PI therapy on DES/IDES levels in patients from RAPID/RAPID Extension. Plasma levels of DES/IDES were measured using high-performance liquid chromatography and tandem mass spectrometry. Correlation between changes in DES/IDES levels and computed tomography (CT) lung density decline was assessed. Analysis showed that DES/IDES levels were significantly reduced versus baseline in patients receiving A1PI at all time points, from month 3 through month 48. A significant increase from baseline in DES/IDES was observed with placebo at month 24 (n=54; 0.016; =0.018). DES/IDES change from baseline was significantly different with A1PI versus placebo at months 3 (-0.021; 95% confidence interval [CI] -0.037, 0.004; =0.026), 12 (-0.040; 95% CI -0.055, 0.025; <0.001), and 24 (-0.052; 95% CI -0.070, 0.034; <0.001). Placebo patients started A1PI therapy at month 24 and showed significant reductions in plasma DES/IDES at months 36 (<0.001) and 48 (<0.001). Reduced elastin degradation was associated with slower lung density decline (=0.005), correlating a chemical index of therapy with an anatomical index by CT. In conclusion, A1PI therapy reduced elastin degradation, including pulmonary elastin, in patients with AATD. These data support using DES/IDES levels as biomarkers to monitor emphysema progression and treatment response.
PubMed: 28848909
DOI: 10.15326/jcopdf.4.1.2016.0156