Receptor-dependent Prorenin Activation and Induction of PAI-1 Expression in Vascular Smooth Muscle Cells

American Journal of Physiology. Endocrinology and Metabolism. Oct, 2008  |  Pubmed ID: 18664599

Although elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remains unclear. Prorenin/renin binding to the prorenin/renin receptor [(p)RR] enhances the efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showing localization of the (p)RR in the aorta to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10(-7) M inactive prorenin, cultured supernatant acquired the ability to generate ANG I from angiotensinogen, indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. Small interfering RNA (siRNA) against the (p)RR blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule plasminogen activator inhibitor (PAI)-1, effects that were blocked by siRNA, but not by the ANG II receptor antagonist saralasin. When inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by treatment with siRNA + saralasin. We conclude that prorenin at high concentration binds the (p)RR on VSMCs and is activated. This activation leads to increased expression of PAI-1 via ANG II-independent and -dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.

Exercise Capacity Improves After Transcatheter Closure of the Fontan Fenestration in Children

Congenital Heart Disease. Jul-Aug, 2008  |  Pubmed ID: 18715459

This study evaluated the aerobic capacity, exercise capacity, and arterial oxygen saturation (O(2)Sat) in children before and after transcatheter Fontan fenestration closure.

The Presence of Bicuspid Aortic Valve Does Not Predict Ventricular Septal Defect Type

American Journal of Medical Genetics. Part A. Dec, 2008  |  Pubmed ID: 19012349

Previous studies have identified an increased incidence of bicuspid aortic valve (BAV) in patients with ventricular septal defect (VSD). Because endocardial cushion remodeling contributes to both the formation of semilunar valves and ventricular septation, we hypothesized that examination of humans with BAV and VSD would identify a specific VSD type. We evaluated VSD type in pediatric patients diagnosed with BAV and VSD (n=82) and compared findings to patients diagnosed with VSD and normal aortic valve morphology (n=429). VSD type was described as conoventricular, muscular, inlet or conoseptal using a clinical taxonomy. Based on the contribution of the outflow tract endocardial cushions to the membranous ventricular septum, we expected patients with BAV to have conoventricular VSD. In both patient groups, conoventricular VSD was most common; however, the prevalence was not significantly different when BAV patients were compared to those with normal aortic valve morphology (67% vs. 57%, P=0.11). The primary finding of this study is that despite a developmental link between semilunar valve formation and ventricular septation during cardiogenesis, there is no clear association between BAV and VSD type. This may be due to phenotypic and genetic heterogeneity of BAV and VSD, other modifying factors as manifested by differences in associated CVM, as well as limitations of the clinical taxonomy of VSD.

Massive Aneurysmal Dilatation of a Depopulated Ureteric Hemodialysis Xenograft

Hemodialysis International. International Symposium on Home Hemodialysis. Jan, 2009  |  Pubmed ID: 19210270

Use of depopulated bovine ureteric xenografts for hemodialysis vascular access has recently been described. Cellular components have been removed, giving a connective tissue matrix which can be neocellularized, retaining native biomechanics. A 24-year-old male with end-stage renal disease from focal segmental glomerulosclerosis presented with particularly difficult vascular access. A depopulated bovine ureteric xenograft was implanted from the left subclavian artery to innominate vein. It became massively aneurysmal, requiring emergency embolization. Biopsy of the graft stained positive for alpha-gal. We believe this is the first reported case of massive aneurysmal dilatation of a depopulated bovine ureteric xenograft.

Lower Weight-for-age Z Score Adversely Affects Hospital Length of Stay After the Bidirectional Glenn Procedure in 100 Infants with a Single Ventricle

The Journal of Thoracic and Cardiovascular Surgery. Aug, 2009  |  Pubmed ID: 19619784

Poor growth has been described in infants with a single ventricle; however, little is known regarding its effect on surgical outcomes. We sought to assess the effect of nutritional status at the time of the bidirectional Glenn procedure on short-term outcomes.

Mechanisms Underlying the Antifibrotic Properties of Noninhibitory PAI-1 (PAI-1R) in Experimental Nephritis

American Journal of Physiology. Renal Physiology. Oct, 2009  |  Pubmed ID: 19625379

Administration of a mutant, noninhibitory PAI-1 (PAI-1R), reduces disease in experimental glomerulonephritis. Here we investigated the importance of vitronectin (Vn) binding, PAI-1 stability and protease binding in this therapeutic effect using a panel of PAI-1 mutants differing in half-life, protease binding, and Vn binding. PAI-1R binds Vn normally but does not inhibit proteases. PAI-1AK has a complete defect in Vn binding but retains full inhibitory activity, with a short half-life similar to wild-type (wt)-PAI-1. Mutant 14-lb is identical to wt-PAI-1 but with a longer half-life. PAI-1K has defective Vn binding, inhibits proteases normally, and has a long half-life. In vitro wt-PAI-1 dramatically inhibited degradation of mesangial cell ECM while the AK mutant had much less effect. Mutants 14-1b and PAI-1K, like wt-PAI-1, inhibited matrix degradation but PAI-1R failed to reverse this inhibition although PAI-1R reversed the wt-PAI-1-induced inhibition of ECM degradation in a plasmin-, time-, and dose-dependent manner. Thus the ability of PAI-1 to inhibit ECM degradation is dependent both on its antiproteinase activity and on maintaining an active conformation achieved either by Vn binding or mutation to a stable form. Administration of these PAI-1 mutants to nephritic rats confirmed the in vitro data; only PAI-1R showed therapeutic effects. PAI-1K did not bind to nephritic kidney, indicating that Vn binding is essential to the therapeutic action of PAI-1R. The ability of PAI-1R to remain bound to Vn even in a high-protease environment is very likely the key to its therapeutic efficacy. Furthermore, because both PAI-1R and 14-1b bound to the nephritic kidney in the same pattern and differ only in their ability to bind proteases, lack of protease inhibition is also keyed to PAI-1R's therapeutic action.

Aortic Arch Recoarctation After the Norwood Stage I Palliation: the Comparative Accuracy of Blood Pressure Cuff and Echocardiographic Doppler Gradients in Detecting Significant Obstruction

Congenital Heart Disease. Nov-Dec, 2009  |  Pubmed ID: 19925537

Aortic arch recoarctation is responsible for significant morbidity and mortality after the Norwood Stage I procedure. Cuff blood pressure (BP) gradients and echocardiographic Doppler gradients are routinely used as noninvasive screening tests for early detection, but accuracy has not been systematically tested. We sought to evaluate the ability of cuff BP and Doppler gradients, measured at routine outpatient clinic visits, to predict significant arch obstruction in single ventricle patients after the Norwood operation.

Infusion of Angiotensin-(1-7) Reduces Glomerulosclerosis Through Counteracting Angiotensin II in Experimental Glomerulonephritis

American Journal of Physiology. Renal Physiology. Mar, 2010  |  Pubmed ID: 20032116

Recent identification of a counterregulatory axis of the renin-angiotensin system, called angiotensin-converting enzyme 2-angiotensin-(1-7) [ANG-(1-7)]-Mas receptor, may offer new targets for the treatment of renal fibrosis. We hypothesized that therapy with ANG-(1-7) would improve glomerulosclerosis through counteracting ANG II in experimental glomerulonephritis. Disease was induced in rats with the monoclonal anti-Thy-1 antibody, OX-7. Based on a three-dose pilot study, 576 microg x kg(-1) x day(-1) ANG-(1-7) was continuously infused from day 1 using osmotic pumps. Measures of glomerulosclerosis include semiquantitative scoring of matrix proteins stained for periodic acid Schiff, collagen I, and fibronectin EDA+ (FN). ANG-(1-7) treatment reduced disease-induced increases in proteinuria by 75%, glomerular periodic acid Schiff staining by 48%, collagen I by 24%, and FN by 25%. The dramatic increases in transforming growth factor-beta1, plasminogen activator inhibitor-1, FN, and collagen I mRNAs seen in disease control animals compared with normal rats were all significantly reduced by ANG-(1-7) administration (P < 0.05). These observations support our hypothesis that ANG-(1-7) has therapeutic potential for reversing glomerulosclerosis. Several results suggest ANG-(1-7) acts by counteracting ANG II effects: 1) renin expression in ANG-(1-7)-treated rats was dramatically increased as it is with ANG II blockade therapy; and 2) in vitro data indicate that ANG II-induced increases in mesangial cell proliferation and plasminogen activator inhibitor-1 overexpression are inhibited by ANG-(1-7) via its binding to a specific receptor known as Mas.

Birth Weight and Prematurity in Infants with Single Ventricle Physiology: Pediatric Heart Network Infant Single Ventricle Trial Screened Population

Congenital Heart Disease. Mar-Apr, 2010  |  Pubmed ID: 20412481

Although congenital heart disease is associated with low birth weight and prematurity, there is little information about these birth outcomes in infants with single ventricle physiology. We describe the birth outcomes (i.e., gestational age and birth weight) in neonates with single ventricle physiology screened for enrollment in the Pediatric Heart Network's Infant Single Ventricle Trial, compare these outcomes with US norms, and examine the association of birth outcomes with anatomic diagnosis and race.

Enalapril in Infants with Single Ventricle: Results of a Multicenter Randomized Trial

Circulation. Jul, 2010  |  Pubmed ID: 20625111

Angiotensin-converting enzyme inhibitor therapy improves clinical outcome and ventricular function in adults with heart failure. Infants with single-ventricle physiology have poor growth and are at risk for abnormalities in ventricular systolic and diastolic function. The ability of angiotensin-converting enzyme inhibitor therapy to preserve ventricular function and improve somatic growth and outcomes in these infants is unknown.

Right Ventricular Function in Adult Patients with Eisenmenger Physiology: Insights from Quantitative Echocardiography

Echocardiography (Mount Kisco, N.Y.). Sep, 2010  |  Pubmed ID: 20849481

The favorable outcomes of Eisenmenger syndrome (ES) relative to other forms of pulmonary arterial hypertension (PAH) have been partially attributed to a unique adaptation of the right ventricle (RV). However, conventional measures of RV function may not adequately express this adaptation.

Full Mouth Rehabilitation with Implant-supported Prostheses for Severe Periodontitis: a Case Report

The Open Dentistry Journal. 2010  |  Pubmed ID: 21339901

Oral rehabilitation for a patient with severe loss of alveolar bone and soft tissue resulting from severe periodontitis presents a challenge to clinicians. Replacing loosening natural teeth with fixed prostheses supported by dental implants often requires either gingival surgery or bone grafting. The outcome of the bone grafting is sometimes unpredictable and requires longer healing time and/ or multiple surgeries. The presence of periodontal inflammation and periapical lesions often delay the placement of bone grafts as well as dental implants. Here we present a clinical case of a patient undergone full mouth reconstruction with implant-supported fixed prostheses. We demonstrated that early placement of implants (three weeks after extractions) with minimal bone grafting may be an alternative to conventional bone grafting followed by implant placement. We believe that primary stability during implant placement may contribute to our success. In addition, composite resin gingival material may be indicated in cases of large fixed implant prostheses as an alternative to pink porcelain.

Defining Salivary Biomarkers Using Mass Spectrometry-based Proteomics: a Systematic Review

Omics : a Journal of Integrative Biology. Jun, 2011  |  Pubmed ID: 21568728

Recent advancements in mass spectrometric proteomics provide a promising result in utilizing saliva to explore biomarkers for diagnostic purposes. However, the issues of specificity or redundancy of disease-associated salivary biomarkers have not been described. This systematic review was therefore aimed to define and summarize disease-related salivary biomarkers identified by mass spectrometry proteomics. Peer-reviewed articles published through July 2009 within three databases were reviewed. Out of 243 articles, 21 studies were selected in this systematic review with conditions including Sjögren's syndrome, squamous cell carcinoma, dental caries, diabetes, breast cancer, periodontitis, gastric cancer, systemic sclerosis, oral lichen planus, bleeding oral cavity, and graft-versus-host disease. The sample size ranged from 3-41 in both diseased and control subjects, with no consensus on sample collection protocol. One hundred eighty biomarkers were identified in total; 87 upregulated, 63 downregulated, and 30 varying based on disease. Except for Sjögren's syndrome, the majority of studies with the same disease produce inconsistent biomarkers. Larger sample size and standardization of sample collection/treatment protocol may improve future studies.

Characterization of Diastolic Dysfunction in Twin-twin Transfusion Syndrome: Association Between Doppler Findings and Ventricular Hypertrophy

Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. Aug, 2011  |  Pubmed ID: 21641772

Twin-twin transfusion syndrome (TTTS) complicates 10% to 15% of monochorionic twin pregnancies. Cardiovascular changes of variable severity, such as ventricular hypertrophy, atrioventricular valve regurgitation, and systolic dysfunction, occur predominantly in recipient twins (RTs). It was the purpose of this study to perform a detailed assessment of ventricular geometry and diastolic function between controls, donor twins (DTs), and RTs.

Combining Angiotensin II Blockade and Renin Receptor Inhibition Results in Enhanced Antifibrotic Effect in Experimental Nephritis

American Journal of Physiology. Renal Physiology. Oct, 2011  |  Pubmed ID: 21795644

The limited antifibrotic effect of therapeutic angiotensin blockade, the fact that angiotensin blockade dramatically elevates renin levels, and recent evidence that renin has an angiotensin-independent, receptor-mediated profibrotic action led us to hypothesize that combining renin receptor inhibition and ANG II blockade would increase the antifibrotic effect of angiotensin blockade alone. Using cultured nephritic glomeruli from rats with anti-Thy-1-induced glomerulonephritis, the maximally effective dose of enalaprilate was determined to be 10(-4) M, which reduced mRNAs for transforming growth factor (TGF)-β1, fibronectin (FN), and plasminogen activator inhibitor-1 (PAI-1) by 49, 65, and 56% and production of TGF-β1 and FN proteins by 60 and 49%, respectively. Disease alone caused 6.8-fold increases in ANG II levels that were reduced 64% with enalaprilate. In contrast, two- and threefold disease-induced increases in renin mRNA and activity were further increased 2- and 3.7-fold with 10(-4) M enalaprilate treatment. Depressing the renin receptor by 80% with small interfering (si) RNA alone reduced fibrotic markers in a manner remarkably similar to enalaprilate alone but had no effect on glomerular renin expression. Enalaprilate and siRNA combination therapy further reduced disease markers. Notably, elevated TGF-β1 and FN production was reduced by 73 and 81%, respectively. These results support the notion of a receptor-mediated profibrotic action of renin, suggest that the limited effectiveness of ANG II blockade may be due, at least in part, to the elevated renin they induce, and support our hypothesis that adding renin receptor inhibitor to ANG II blockade in patients may have therapeutic potential.

Fabrication of a Maxillary Implant Retained Overdenture Using an Existing Subperiostal Implant: a Clinical Report

The Open Dentistry Journal. 2011  |  Pubmed ID: 21804901

Subperiosteal implants used to be prescribed to partially and fully edentulous patients to restore occlusion and esthetics prior to the emergence of the more successful endosseous implants that are used today. Because subperiosteal implants had a high incidence of failure, difficulty of placement, and post-operative complications, the use of subperiosteal implants declined significantly. However, some subperiostal implants placed 20-30 years ago still survive. Little information is available in the literature on how to treat patients whose subperiosteal implants still remain. This clinical case report thereby describes a treatment for a patient with a maxillary subperiosteal implant placed 23 years ago. The patient was offered a treatment option that included surgical implant removal, bone grafting and placement of endosseous implants to support a new maxillary overdenture. This treatment plan was not feasible due to the financial constraints of the patient and the complexity of the treatment. The patient chose a more conservative treatment plan, preserving the existing implant. The existing maxillary subperiosteal implant was restored with MICRO ERA attachments and a maxillary implant-retained overdenture was fabricated. The patient was satisfied with the esthetics and functional aspects of the treatment. No further peri-implant bone loss or other complications were found after a six-month recall. This clinical report suggests an alternative treatment plan for patients with existing subperiosteal implants that wish to avoid complex surgical procedures.

Right Ventricular Function with Standard and Speckle-Tracking Echocardiography and Clinical Events in Adults with D-Transposition of the Great Arteries Post Atrial Switch

Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. Dec, 2011  |  Pubmed ID: 22196884

BACKGROUND: The prognostic value of deformation parameters of the systemic right ventricle in adults with D-transposition of the great arteries and prior atrial switch has not been reported. METHODS: Sixty-four adults with D-transposition of the great arteries and prior atrial switch (mean age, 29 ± 6 years; 22 women; mean right ventricular [RV] fractional area change, 22.9 ± 7.5%; 31 with pacemakers at baseline) and no histories of heart failure or ventricular tachycardia were prospectively evaluated. Global longitudinal strain (GS), global systolic strain rate (GSRs), and global early diastolic strain rate (GSRe) of the right ventricle were measured using speckle tracking from apical views and compared with standard parameters of RV function (fractional area change, tricuspid annular plane systolic excursion, tissue Doppler velocities, and isovolumic acceleration) for association with and potential prediction of clinical events, defined as incident stage C heart failure or ventricular tachycardia. RESULTS: Baseline RV GS, GSRs, and GSRe were -12.5 ± 3.0%, -0.59 ± 0.14 sec(-1), and 0.68 ± 0.22 sec(-1), respectively. After a median of 2.4 years (interquartile range, 1.5-4.1 years), 12 patients (19%) presented with clinical events (heart failure in 11 patients, ventricular tachycardia in one patient). In Cox models, RV GS had the strongest association with clinical events (hazard ratio [HR] per 1%, 1.35; 95% confidence interval [CI], 1.14-1.58; P < .001), followed by GSRs (HR per 0.01 sec(-1), 1.06; 95% CI, 1.02-1.11; P = .006), GSRe (HR per -0.01 sec(-1), 1.04; 95% CI, 1.00-1.07; P = .031), and fractional area change (HR per -1%, 1.08; 95% CI, 1.00-1.17; P = .047). Other measures of RV function were not significantly associated with risk for events. In receiver operating characteristic analysis, RV GS ≥ -10% optimally predicted future events (C = 0.83; 95% CI, 0.71-0.91; P < .001). CONCLUSIONS: Reduced longitudinal GS of the systemic right ventricle is associated with increased risk for clinical events among patients with D-transposition of the great arteries and prior atrial switch.

A Juvenile Murine Heart Failure Model of Pressure Overload

Pediatric Cardiology. Feb, 2011  |  Pubmed ID: 21104078

Persistent pressure overload can cause cardiac hypertrophy and progressive heart failure (HF). The authors developed a pressure-overload HF model of juvenile mice to study the cardiac response to pressure overload that may be applicable to clinical processes in children. Severe thoracic aortic banding (sTAB) was performed using a 28-gauge needle for 40 juvenile (age, 3 weeks) and 47 adult (age, 6 weeks) C57BL/6 male mice. To monitor the structural and functional changes, M-mode echocardiography was performed for conscious mice that had undergone sTAB and sham operation. Cardiac hypertrophy, dilation, and HF occurred in both juvenile and adult mice after sTAB. Compared with adults, juvenile HF is characterized by greater impairment of ventricular contractility and less hypertrophy. In addition, juvenile mice had significantly higher rates of survival than adult mice during the early postoperative weeks. Consistent with clinical HF seen in children, juvenile banded mice demonstrated a lower growth rate than either adult banded mice or juvenile control mice that had sham operations. The authors first developed a juvenile murine model of pressure-overload HF. Learning the unique characteristics of pressure-overload HF in juveniles should aid in understanding age-specific pathologic changes for HF development in children.

Isolated Innominate Artery from the Main Pulmonary Artery in DiGeorge Syndrome

Journal of the American College of Cardiology. Feb, 2011  |  Pubmed ID: 21292136

Exploring Salivary Proteomes in Edentulous Patients with Type 2 Diabetes

Molecular BioSystems. Feb, 2012  |  Pubmed ID: 22314925

Type 2 diabetes and tooth loss are linked both epidemiologically and pathophysiologically. We applied label-free differential protein expression analysis using multidimensional liquid chromatography/tandem mass spectrometry (2D-LC-MS/MS) to explore the proteomic profile of saliva samples collected from selected type 2 diabetic edentulous patients and non-diabetic controls. Ninety-six peptides corresponding to 52 proteins were differentially expressed between the diabetic edentulous patients and controls (p < 0.05). Some diabetes-related inflammatory biomarkers including glyceraldehyde-3-phosphate dehydrogenase and serum amyloid A were detected with levels increased in diabetic samples. Other biomarkers including amylase, palate, lung and nasal epithelium associated protein (PLUNC), and serotransferrin levels were decreased in diabetic samples. In contrast with previous findings, salivary carbonic anhydrase 6 and alpha-2 macroglobulin levels, however, were decreased in this diabetic patient population. Cluster analysis and principle component analysis demonstrated a differential pattern of protein biomarker expression between diabetic and control subjects. Western blot analysis was completed to confirm the relatively lower expression level of two biomarkers, including PLUNC and amylase in the diabetic group compared to control subjects. The presence of salivary biomarkers specific for diabetes in edentulous subjects mimics those in serum, especially those related to inflammatory/lipid metabolism. While this exploratory study requires further validation with a larger population, it provides proof-of-principle for salivary proteomics for edentulous subjects with diabetes.