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Given current evidence supporting a genetic predisposition for pelvic organ prolapse, we conducted a systematic review of published literature on the genetic epidemiology of pelvic organ prolapse. Inclusion criteria were linkage studies, candidate gene association and genome-wide association studies in adult women published in English and indexed in PubMed through Dec. 2012, with no limit on date of publication. Methodology adhered to the PRISMA guidelines. Data were systematically extracted by 2 reviewers and graded by the Venice criteria for studies of genetic associations. A metaanalysis was performed on all single nucleotide polymorphisms evaluated by 2 or more studies with similar methodology. The metaanalysis suggests that collagen type 3 alpha 1 (COL3A1) rs1800255 genotype AA is associated with pelvic organ prolapse (odds ratio, 4.79; 95% confidence interval, 1.91-11.98; P = .001) compared with the reference genotype GG in populations of Asian and Dutch women. There was little evidence of heterogeneity for rs1800255 (P value for heterogeneity = .94; proportion of variance because of heterogeneity, I(2) = 0.00%). There was insufficient evidence to determine whether other single nucleotide polymorphisms evaluated by 2 or more papers were associated with pelvic organ prolapse. An association with pelvic organ prolapse was seen in individual studies for estrogen receptor alpha (ER-α) rs2228480 GA, COL3A1 exon 31, chromosome 9q21 (heterogeneity logarithm of the odds score 3.41) as well as 6 single nucleotide polymorphisms identified by a genome-wide association study. Overall, individual studies were of small sample size and often of poor quality. Future studies would benefit from more rigorous study design as outlined in the Venice recommendations.
Copyright © 2014 Elsevier Inc. All rights reserved.
Vascular Ehlers-Danlos syndrome (EDS) type IV is the most severe form of EDS. In many cases the disease is caused by a point mutation of Gly in type III collagen. A slower folding of the collagen helix is a potential cause for over-modifications. However, little is known about the rate of folding of type III collagen in patients with EDS. To understand the molecular mechanism of the effect of mutations, a system was developed for bacterial production of homotrimeric model polypeptides. The C-terminal quarter, 252 residues, of the natural human type III collagen was attached to (GPP)7 with the type XIX collagen trimerization domain (NC2). The natural collagen domain forms a triple helical structure without 4-hydroxylation of proline at a low temperature. At 33 °C, the natural collagenous part is denatured, but the C-terminal (GPP)7-NC2 remains intact. Switching to a low temperature triggers the folding of the type III collagen domain in a zipper-like fashion that resembles the natural process. We used this system for the two known EDS mutations (Gly-to-Val) in the middle at Gly-910 and at the C terminus at Gly-1018. In addition, wild-type and Gly-to-Ala mutants were made. The mutations significantly slow down the overall rate of triple helix formation. The effect of the Gly-to-Val mutation is much more severe compared with Gly-to-Ala. This is the first report on the folding of collagen with EDS mutations, which demonstrates local delays in the triple helix propagation around the mutated residue.
BACKGROUND/AIMS - Renal interstitial fibrosis is a final common pathway of all chronic, progressive kidney diseases. Peritubular capillary rarefaction is strongly correlated with fibrosis. The adherens junction protein vascular endothelial cadherin (VE-cadherin) is thought to play a critical role in vascular integrity. We hypothesized that VE-cadherin modulates the renal microcirculation during fibrogenesis and ultimately affects renal fibrosis.
METHODS - Unilateral ureteral obstruction (UUO) was used as a renal fibrosis model in VE-cadherin heterozygote (VE+/-) and wild-type (WT) mice, and the kidneys were harvested at days 3, 7, and 14. Peritubular capillary changes and fibrogenesis were investigated.
RESULTS - VE+/- mice had lower levels of VE-cadherin protein than WT mice at 3 and 7, but not 14 days after UUO. Vascular permeability was significantly greater in VE+/- mice 7 days after UUO, while peritubular capillary density was not significantly different in VE+/- and WT mice. Interstitial myofibroblast numbers and collagen I and III mRNA levels were significantly higher in VE+/- mice, consistent with a stronger early fibrogenic response. Expression of the pericyte marker neuron-glial antigen 2 was upregulated after UUO, but was not greater in VE+/- mice compared to the WT mice.
CONCLUSION - Our data suggest that VE-cadherin controls vascular permeability and limits fibrogenesis after UUO.
Copyright © 2011 S. Karger AG, Basel.
OBJECTIVE - The hypothesis that high-fat (HF) feeding causes skeletal muscle extracellular matrix (ECM) remodeling in C57BL/6J mice and that this remodeling contributes to diet-induced muscle insulin resistance (IR) through the collagen receptor integrin α(2)β(1) was tested.
RESEARCH DESIGN AND METHODS - The association between IR and ECM remodeling was studied in mice fed chow or HF diet. Specific genetic and pharmacological murine models were used to study effects of HF feeding on ECM in the absence of IR. The role of ECM-integrin interaction in IR was studied using hyperinsulinemic-euglycemic clamps on integrin α(2)β(1)-null (itga2(-/-)), integrin α(1)β(1)-null (itga1(-/-)), and wild-type littermate mice fed chow or HF. Integrin α(2)β(1) and integrin α(1)β(1) signaling pathways have opposing actions.
RESULTS - HF-fed mice had IR and increased muscle collagen (Col) III and ColIV protein; the former was associated with increased transcript, whereas the latter was associated with reduced matrix metalloproteinase 9 activity. Rescue of muscle IR by genetic muscle-specific mitochondria-targeted catalase overexpression or by the phosphodiesterase 5a inhibitor, sildenafil, reversed HF feeding effects on ECM remodeling and increased muscle vascularity. Collagen remained elevated in HF-fed itga2(-/-) mice. Nevertheless, muscle insulin action and vascularity were increased. Muscle IR in HF-fed itga1(-/-) mice was unchanged. Insulin sensitivity in chow-fed itga1(-/-) and itga2(-/-) mice was not different from wild-type littermates.
CONCLUSIONS - ECM collagen expansion is tightly associated with muscle IR. Studies with itga2(-/-) mice provide mechanistic insight for this association by showing that the link between muscle IR and increased collagen can be uncoupled by the absence of collagen-integrin α(2)β(1) interaction.
Angiotensin II (Ang II) is a major contributor to the progression of renal fibrosis. Wang and colleagues provide evidence that signaling through the prolyl-4-hydroxylase domain (PHD)-hypoxia-inducible factor-1 (HIF-1) pathway mediates profibrotic effects of Ang II in rat renal medullary interstitial cells under normoxic conditions, thus placing the HIF oxygen-sensing pathway into the center of an Ang II-induced profibrotic signaling cascade.
BACKGROUND - The diagnosis of acute lung injury (ALI) is based on a consensus clinical definition. Despite the simplicity of this definition, ALI remains underdiagnosed and undertreated. Severe trauma is a well-described cause of ALI that represents a relatively homogeneous subset of patients with ALI. The aims of this study were to develop a panel of plasma biomarkers to facilitate diagnosis of trauma-induced ALI and to enhance our understanding of the pathogenesis of human ALI.
METHODS - A retrospective nested case control of 192 patients admitted to the trauma intensive care unit at a university hospital between 2002 and 2006. We compared 107 patients with ALI to 85 patients without ALI. Plasma was collected within 72 hours of intensive care unit admission. Twenty-one plasma biomarkers were measured in duplicate in each plasma sample.
RESULTS - Patients with ALI had higher severity of illness scores, more days of mechanical ventilation, longer hospital stays, and higher mortality versus controls. Seven biomarkers (receptor for advanced glycation end products, procollagen peptide III, brain natriuretic peptide, angiopoietin-2, interleukin-10, tumor necrosis factor alpha, and interleukin-8) had a high diagnostic accuracy as reflected by the area under the receiver operating characteristic curve of 0.86 (95% confidence interval, 0.82-0.92) in differentiating ALI from controls.
CONCLUSIONS - A model using seven plasma biomarkers had a high diagnostic accuracy in differentiating patients with trauma-induced ALI from trauma patients without ALI. In addition, use of a panel of biomarkers provides insight into the likely importance of alveolar epithelial injury in the pathogenesis of early ALI.
OBJECTIVE - Hyperhomocysteinemia, neurohormonal activation, inflammation and altered fibrinolysis have been linked to atherothrombosis as well as to myocardial fibrosis and heart failure. Hence, we related a panel of biomarkers representing these pathways to plasma markers of collagen metabolism in a large community-based sample.
METHODS - We related nine biomarkers representing select biologic pathways (independent variables: C-reactive protein, B-type natriuretic peptide, N-terminal proatrial natriuretic peptide, aldosterone, renin, fibrinogen, D-dimer, plasminogen activator inhibitor-1 and homocysteine) to three plasma markers of collagen turnover [dependent variables, separate models for each: aminoterminal propeptide of type III collagen, tissue inhibitor of metalloproteinases-1 and matrix metalloproteinase-9 (present versus absent)] in 921 Framingham Heart study participants (mean age 57 years; 58% women). Participants were separated a priori into those with left ventricular end-diastolic dimensions and wall thickness below sex-specific median values (referent group) and either measure at least 90th sex-specific percentile ('remodeled' group). We used stepwise multivariable regression analysis adjusting for cardiovascular risk factors to relate the panel of systemic biomarkers to the three biomarkers of collagen metabolism.
RESULTS - Plasma homocysteine was positively related to all three markers of collagen metabolism in the remodeled group and to aminoterminal propeptide of type III collagen and tissue inhibitor of metalloproteinases-1 in the referent group. Plasminogen activator inhibitor-1 was positively related to aminoterminal propeptide of type III collagen and tissue inhibitor of metalloproteinases-1 in both groups, whereas the natriuretic peptides were associated positively with these collagen markers in the referent group.
CONCLUSION - In our large community-based sample, plasma homocysteine and plasminogen activator inhibitor-1 were positively related to circulating collagen biomarkers, consistent with experimental studies implicating these pathways in cardiovascular collagen turnover.
Type III collagen is a critical collagen that comprises extensible connective tissue such as skin, lung, and the vascular system. Mutations in the type III collagen gene, COL3A1, are associated with the most severe forms of Ehlers-Danlos syndrome. A characteristic feature of type III collagen is the presence of a stabilizing C-terminal cystine knot. Crystal structures of collagen triple helices reported so far contain artificial sequences like (Gly-Pro-Pro)(n) or (Gly-Pro-Hyp)(n). To gain insight into the structural properties exhibited by the natural type III collagen triple helix, we synthesized, crystallized, and determined the structure of a 12-triplet repeating peptide containing the natural type III collagen sequence from residues 991 to 1032 including the C-terminal cystine knot region, to 2.3A resolution. This represents the longest collagen triple helical structure determined to date with a native sequence. Strikingly, the Gly(991)-Gly(1032) structure reveals that the central non-imino acid-containing region adopts 10/3 superhelical properties, whereas the imino acid rich N- and C-terminal regions adhere to a 7/2 superhelical conformation. The structure is consistent with two models for the cystine knot; however, the poor density for the majority of this region suggests that multiple conformations may be adopted. The structure shows that the multiple non-imino acids make several types of direct intrahelical as well as interhelical contacts. The looser superhelical structure of the non-imino acid region of collagen triple helices combined with the extra contacts afforded by ionic and polar residues likely play a role in fibrillar assembly and interactions with other extracellular components.
Collagen consists of repetitive Gly-Xaa-Yaa tripeptide units with proline and hydroxyproline frequently found in the Xaa and Yaa position, respectively. This sequence motif allows the formation of a highly regular triple helix that is stabilized by steric (entropic) restrictions in the constituent polyproline-II-helices and backbone hydrogen bonds between the three strands. Concentration-dependent association reactions and slow prolyl isomerization steps have been identified as major rate-limiting processes during collagen folding. To gain information on the dynamics of triple-helix formation in the absence of these slow reactions, we performed stopped-flow double-jump experiments on cross-linked fragments derived from human type III collagen. This technique allowed us to measure concentration-independent folding kinetics starting from unfolded chains with all peptide bonds in the trans conformation. The results show that triple-helix formation occurs with a rate constant of 113 +/- 20 s(-1) at 3.7 degrees C and is virtually independent of temperature, indicating a purely entropic barrier. Comparison of the effect of guanidinium chloride on folding kinetics and stability reveals that the rate-limiting step is represented by bringing 10 consecutive tripeptide units (3.3 per strand) into a triple-helical conformation. The following addition of tripeptide units occurs on a much faster time scale and cannot be observed experimentally. These results support an entropy-controlled zipper-like nucleation/growth mechanism for collagen triple-helix formation.
OBJECTIVE - To test the hypothesis that pharmacological plasminogen activator inhibitor (PAI)-1 inhibition protects against renin-angiotensin-aldosterone system-induced cardiovascular injury, the effect of a novel orally active small-molecule PAI-1 inhibitor, PAI-039, was examined in a mouse model of angiotensin (Ang) II-induced vascular remodeling and cardiac fibrosis.
METHODS AND RESULTS - Uninephrectomized male C57BL/6J mice were randomized to vehicle subcutaneus, Ang II (1 mug/h) subcutaneous, vehicle+PAI-039 (1 mg/g chow), or Ang II+PAI-039 during high-salt intake for 8 weeks. Ang II caused significant medial, adventitial, and aortic wall thickening compared with vehicle. PAI-039 attenuated Ang II-induced aortic remodeling without altering the pressor response to Ang II. Ang II increased heart/body weight ratio and cardiac fibrosis. PAI-039 did not attenuate the effect of Ang II on cardiac hypertrophy and increased fibrosis. The effect of PAI-039 on Ang II/salt-induced aortic remodeling and cardiac fibrosis was comparable to the effect of genetic PAI-1 deficiency. Ang II increased aortic mRNA expression of PAI-1, collagen I, collagen III, fibronectin, osteopontin, monocyte chemoattractant protein-1, and F4/80; PAI-039 significantly decreased the Ang II-induced increase in aortic osteopontin expression at 8 weeks.
CONCLUSIONS - This study demonstrates that pharmacological inhibition of PAI-1 protects against Ang II-induced aortic remodeling. Future studies are needed to determine whether the interactive effect of Ang II/salt and reduced PAI-1 activity on cardiac fibrosis is species-specific. In this study, the effect of pharmacological PAI-1 inhibition in a mouse model of Ang II-induced vascular remodeling and cardiac fibrosis was examined. PAI-1 inhibition significantly attenuated Ang II-induced aortic medial and wall thickening, but not cardiac hypertrophy, and enhanced Ang II/salt-induced cardiac fibrosis.