A supramolecular polymer-collagen microparticle slurry for bone regeneration with minimal growth factor.

Recombinant bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive growth factor that can promote bone regeneration for challenging skeletal repair and even for ectopic bone formation in spinal fusion procedures. However, serious clinical side effects related to supraphysiological dosing highlight the need for advances in novel biomaterials that can significantly reduce the amount of this biologic. Novel biomaterials could not only reduce clinical side effects but also expand the indications for use of BMP-2, while at the same time lowering the cost of such procedures. To achieve this objective, we have developed a slurry containing a known supramolecular polymer that potentiates BMP-2 signaling and porous collagen microparticles. This slurry exhibits a paste-like consistency that stiffens into an elastic gel upon implantation making it ideal for minimally invasive procedures. We carried out in vivo evaluation of the novel biomaterial in the rabbit posterolateral spine fusion model, and discovered efficacy at unprecedented ultra-low BMP-2 doses (5 µg/implant). This dose reduces the growth factor requirement by more than 100-fold relative to current clinical products. This observation is significant given that spinal fusion involves ectopic bone formation and the rabbit model is known to be predictive of human efficacy. We expect the novel biomaterial can expand BMP-2 indications for difficult cases requiring large volumes of bone formation or involving patients with underlying conditions that compromise bone regeneration.

A Chemotactic Functional Scaffold with VEGF-Releasing Peptide Amphiphiles Facilitates Bone Regeneration by BMP-2 in a Large-Scale Rodent Cranial Defect Model.

BACKGROUND: Current common techniques for repairing calvarial defects by autologous bone grafting and alloplastic implants have significant limitations. In this study, the authors investigated a novel alternative approach to bone repair based on peptide amphiphile nanofiber gels that are engineered to control the release of vascular endothelial growth factor (VEGF) to recruit circulating stem cells to a site of bone regeneration and facilitate bone healing by bone morphogenetic protein-2 (BMP-2). METHODS: VEGF release kinetics from peptide amphiphile gels were evaluated. Chemotactic functional scaffolds were fabricated by combining collagen sponges with peptide amphiphile gels containing VEGF. The in vitro and in vivo chemotactic activities of the scaffolds were evaluated by measuring mesenchymal stem cell migration, and angiogenic capability of the scaffolds was also evaluated. Large-scale rodent cranial bone defects were created to evaluate bone regeneration after implanting the scaffolds and other control materials. RESULTS: VEGF was released from peptide amphiphile in a controlled-release manner. In vitro migration of mesenchymal stem cells was significantly greater when exposed to chemotactic functional scaffolds compared to control scaffolds. In vivo chemotaxis was evidenced by migration of tracer-labeled mesenchymal stem cells to the chemotactic functional scaffolds. Chemotactic functional scaffolds showed significantly increased angiogenesis in vivo. Successful bone regeneration was noted in the defects treated with chemotactic functional scaffolds and BMP-2. CONCLUSIONS: The authors' observations suggest that this bioengineered construct successfully acts as a chemoattractant for circulating mesenchymal stem cells because of controlled release of VEGF from the peptide amphiphile gels. The chemotactic functional scaffolds may play a role in the future design of clinically relevant bone graft substitutes for large-scale bone defects.

Bone Morphogenetic Protein 4 Targeting Glioma Stem-Like Cells for Malignant Glioma Treatment: Latest Advances and Implications for Clinical Application.

Malignant gliomas are heterogeneous neoplasms. Glioma stem-like cells (GSCs) are undifferentiated and self-renewing cells that develop and maintain these tumors. These cells are the main population that resist current therapies. Genomic and epigenomic analyses has identified various molecular subtypes. Bone morphogenetic protein 4 (BMP4) reduces the number of GSCs through differentiation and induction of apoptosis, thus increasing therapeutic sensitivity. However, the short half-life of BMP4 impedes its clinical application. We previously reviewed BMP4 signaling in central nervous system development and glioma tumorigenesis and its potential as a treatment target in human gliomas. Recent advances in understanding both adult and pediatric malignant gliomas highlight critical roles of BMP4 signaling pathways in the regulation of tumor biology, and indicates its potential as a therapeutic molecule. Furthermore, significant progress has been made on synthesizing BMP4 biocompatible delivery materials, which can bind to and markedly extend BMP4 half-life. Here, we review current research associated with BMP4 in brain tumors, with an emphasis on pediatric malignant gliomas. We also summarize BMP4 delivery strategies, highlighting biocompatible BMP4 binding peptide amphiphile nanostructures as promising novel delivery platforms for treatment of these devastating tumors.

Bioactive peptide amphiphile nanofiber gels enhance burn wound healing.

BACKGROUND: Burns are physically debilitating and potentially fatal injuries. The standard-of-care for burn wounds is the coverage with gauze dressings designed to minimize trauma to the regenerating epidermis and dermis during dressing changes. However, deep partial- and full-thickness burns always heal slowly when standard wound care alone is performed. We have previously reported that peptide amphiphile (PA) gels, pH-induced self-assembling nanostructured fibrous scaffolds, promote cell proliferation and have great potential in regenerative medicine for rapid repair of tissues. In this study, we hypothesized that the PA gels are capable of accelerating wound healing in burn injury. METHODS: Artificially generated thermally damaged fibroblasts and human umbilical vein endothelial cells were seeded onto the various PA nanofiber gels including bioactive and nonbioactive peptide sequences. Cell proliferation was assessed at different time points, and thermally damaged fibroblasts and HUVECs manifested increased proliferation with time when cultured with various PA gels. To determine in vivo effects, burn wounds of rats were treated with the bioactive Arg-Gly-Asp-Ser (RGDS)-modified gel that showed greater cell proliferation in vitro. The wound closure was observed, and skin samples were harvested for histologic evaluation. RESULTS: Cell proliferation using the RGDS-PA gel was significantly higher than that observed in other gels. The RGDS-PA gel significantly enhanced re-epithelialization during the burn wound healing process between days 7 and 28. Application of PA gels accelerates the recovery of deep partial-thickness burn wounds by stimulation of fibroblasts and the creation of an environment conducive to epithelial cell proliferation and wound closure. CONCLUSIONS: This biomaterial represents a new therapeutic strategy to overcome current clinical challenges in the treatment of injuries resulting from burns.

Reversible self-assembly of superstructured networks.

Soft structures in nature, such as protein assemblies, can organize reversibly into functional and often hierarchical architectures through noncovalent interactions. Molecularly encoding this dynamic capability in synthetic materials has remained an elusive goal. We report on hydrogels of peptide-DNA conjugates and peptides that organize into superstructures of intertwined filaments that disassemble upon the addition of molecules or changes in charge density. Experiments and simulations demonstrate that this response requires large-scale spatial redistribution of molecules directed by strong noncovalent interactions among them. Simulations also suggest that the chemically reversible structures can only occur within a limited range of supramolecular cohesive energies. Storage moduli of the hydrogels change reversibly as superstructures form and disappear, as does the phenotype of neural cells in contact with these materials.

Electrophysiological assessment of a peptide amphiphile nanofiber nerve graft for facial nerve repair.

Facial nerve injury can cause severe long-term physical and psychological morbidity. There are limited repair options for an acutely transected facial nerve not amenable to primary neurorrhaphy. We hypothesize that a peptide amphiphile nanofiber neurograft may provide the nanostructure necessary to guide organized neural regeneration. Five experimental groups were compared, animals with (1) an intact nerve, (2) following resection of a nerve segment, and following resection and immediate repair with either a (3) autograft (using the resected nerve segment), (4) neurograft, or (5) empty conduit. The buccal branch of the rat facial nerve was directly stimulated with charge balanced biphasic electrical current pulses at different current amplitudes whereas nerve compound action potentials (nCAPs) and electromygraphic responses were recorded. After 8 weeks, the proximal buccal branch was surgically reexposed and electrically evoked nCAPs were recorded for groups 1-5. As expected, the intact nerves required significantly lower current amplitudes to evoke an nCAP than those repaired with the neurograft and autograft nerves. For other electrophysiologic parameters such as latency and maximum nCAP, there was no significant difference between the intact, autograft, and neurograft groups. The resected group had variable responses to electrical stimulation, and the empty tube group was electrically silent. Immunohistochemical analysis and transmission electron microscopy confirmed myelinated neural regeneration. This study demonstrates that the neuroregenerative capability of peptide amphiphile nanofiber neurografts is similar to the current clinical gold standard method of repair and holds potential as an off-the-shelf solution for facial reanimation and potentially peripheral nerve repair.

Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation.

Muscle stem cells are a potent cell population dedicated to efficacious skeletal muscle regeneration, but their therapeutic utility is currently limited by mode of delivery. We developed a cell delivery strategy based on a supramolecular liquid crystal formed by peptide amphiphiles (PAs) that encapsulates cells and growth factors within a muscle-like unidirectionally ordered environment of nanofibers. The stiffness of the PA scaffolds, dependent on amino acid sequence, was found to determine the macroscopic degree of cell alignment templated by the nanofibers in vitro. Furthermore, these PA scaffolds support myogenic progenitor cell survival and proliferation and they can be optimized to induce cell differentiation and maturation. We engineered an in vivo delivery system to assemble scaffolds by injection of a PA solution that enabled coalignment of scaffold nanofibers with endogenous myofibers. These scaffolds locally retained growth factors, displayed degradation rates matching the time course of muscle tissue regeneration, and markedly enhanced the engraftment of muscle stem cells in injured and noninjured muscles in mice.

Sulfated glycopeptide nanostructures for multipotent protein activation.

Biological systems have evolved to utilize numerous proteins with capacity to bind polysaccharides for the purpose of optimizing their function. A well-known subset of these proteins with binding domains for the highly diverse sulfated polysaccharides are important growth factors involved in biological development and tissue repair. We report here on supramolecular sulfated glycopeptide nanostructures, which display a trisulfated monosaccharide on their surfaces and bind five critical proteins with different polysaccharide-binding domains. Binding does not disrupt the filamentous shape of the nanostructures or their internal ß-sheet backbone, but must involve accessible adaptive configurations to interact with such different proteins. The glycopeptide nanostructures amplified signalling of bone morphogenetic protein 2 significantly more than the natural sulfated polysaccharide heparin, and promoted regeneration of bone in the spine with a protein dose that is 100-fold lower than that required in the animal model. These highly bioactive nanostructures may enable many therapies in the future involving proteins.

Prevalence of vertebral artery origin stenosis and occlusion in outpatient extracranial ultrasonography.

BACKGROUND AND PURPOSE: Most data on the prevalence of vertebral artery origin (VAo) disease is derived from hospital-based studies of patients with posterior circulation strokes and TIA. The prevalence of VAo disease in patients without posterior circulation symptoms or asymptomatic patients is poorly characterized. Our objective was to examine the prevalence of VAo stenosis and occlusion in consecutive patients, presenting for extracranial ultrasonography to an outpatient laboratory. METHODS: We retrospectively identified 2490 consecutive extracranial duplex studies performed in an ambulatory neurovascular ultrasound laboratory. All studies were reviewed for the presence of >50% VAo stenosis, defined as a PSV > 114 cm/s, and VA occlusion. We also reviewed the prevalence of >50% carotid stenosis, defined as a PSV > 120 cm/s, in the same population, to draw comparisons with VAo stenosis prevalence. RESULTS: We identified right VAo stenosis in 52/1955 (2.7%) and occlusion in 74/1955 (3.9%) and left-sided VAo stenosis in 45/1973 (2.5%) and occlusion in 64/1973 (3.6%). The prevalence of having any (either right or left) VAo stenosis or occlusion was 8.2% and 1.4% had bilateral VAo stenosis or occlusion. Right carotid stenosis and occlusion was found in 236/2399 (9.8%) and 53/2399 (2.2%) and left carotid stenosis and occlusion in 236/2397 (9.8%) and 45/2397 (1.9%), respectively. Any carotid disease, either right or left, was present in 18.9% and 4.7% had bilateral carotid disease. CONCLUSION: Although less prevalent than cervical carotid disease, we found that approximately 8% of patients who presented to an ambulatory ultrasound laboratory had >50% VAo disease.

Self-assembling hydrogel scaffolds for photocatalytic hydrogen production.

Integration into a soft material of all the molecular components necessary to generate storable fuels is an interesting target in supramolecular chemistry. The concept is inspired by the internal structure of photosynthetic organelles, such as plant chloroplasts, which colocalize molecules involved in light absorption, charge transport and catalysis to create chemical bonds using light energy. We report here on the light-driven production of hydrogen inside a hydrogel scaffold built by the supramolecular self-assembly of a perylene monoimide amphiphile. The charged ribbons formed can electrostatically attract a nickel-based catalyst, and electrolyte screening promotes gelation. We found the emergent phenomenon that screening by the catalyst or the electrolytes led to two-dimensional crystallization of the chromophore assemblies and enhanced the electronic coupling among the molecules. Photocatalytic production of hydrogen is observed in the three-dimensional environment of the hydrogel scaffold and the material is easily placed on surfaces or in the pores of solid supports.

Prevalence of vertebral artery origin stenosis and occlusion in outpatient extracranial ultrasonography.

BACKGROUND AND PURPOSE: Vertebral artery origin stenosis prevalence. Most data on the prevalence of vertebral artery origin (VAo) disease is derived from hospital-based studies of patients with posterior circulation strokes and TIA. The prevalence of VAo disease in patients without posterior circulation symptoms or asymptomatic patients is poorly characterized. Our objective was to examine the prevalence of VAo stenosis and occlusion in consecutive patients, presenting for extracranial ultrasonography at an outpatient laboratory. METHODS: We retrospectively identified 2490 consecutive extracranial duplex studies performed in an ambulatory neurovascular ultrasound laboratory. All studies were reviewed for the presence of >50% VAo stenosis, defined as a PSV > 114 cm/s, and VA occlusion. We also reviewed the prevalence of >50% carotid stenosis, defined as a PSV > 120 cm/s, in the same population, to draw comparisons with VAo stenosis prevalence. RESULTS: We identified right VAo stenosis in 52/1955 (2.7%) and occlusion in 74/ 1955 (3.9%) and left-sided VAo stenosis in 45/1973 (2.5%) and occlusion in 64/1973 (3.6%). The prevalence of having any (either right or left) VAo stenosis or occlusion was 8.2% and 1.4% had bilateral VAo stenosis or occlusion. Right carotid stenosis and occlusion was found in 236/2399 (9.8%) and 53/2399 (2.2%), and left carotid stenosis and occlusion in 236/2397 (9.8%) and 45/2397 (1.9%), respectively. Any carotid disease, either right or left, was present in 18.9% and 4.7% had bilateral carotid disease. CONCLUSION: Although less prevalent than cervical carotid disease, we found that approximately 8% of patients who reported to an ambulatory ultrasound laboratory had >50% VAo disease.

A bioengineered peripheral nerve construct using aligned peptide amphiphile nanofibers.

Peripheral nerve injuries can result in lifelong disability. Primary coaptation is the treatment of choice when the gap between transected nerve ends is short. Long nerve gaps seen in more complex injuries often require autologous nerve grafts or nerve conduits implemented into the repair. Nerve grafts, however, cause morbidity and functional loss at donor sites, which are limited in number. Nerve conduits, in turn, lack an internal scaffold to support and guide axonal regeneration, resulting in decreased efficacy over longer nerve gap lengths. By comparison, peptide amphiphiles (PAs) are molecules that can self-assemble into nanofibers, which can be aligned to mimic the native architecture of peripheral nerve. As such, they represent a potential substrate for use in a bioengineered nerve graft substitute. To examine this, we cultured Schwann cells with bioactive PAs (RGDS-PA, IKVAV-PA) to determine their ability to attach to and proliferate within the biomaterial. Next, we devised a PA construct for use in a peripheral nerve critical sized defect model. Rat sciatic nerve defects were created and reconstructed with autologous nerve, PLGA conduits filled with various forms of aligned PAs, or left unrepaired. Motor and sensory recovery were determined and compared among groups. Our results demonstrate that Schwann cells are able to adhere to and proliferate in aligned PA gels, with greater efficacy in bioactive PAs compared to the backbone-PA alone. In vivo testing revealed recovery of motor and sensory function in animals treated with conduit/PA constructs comparable to animals treated with autologous nerve grafts. Functional recovery in conduit/PA and autologous graft groups was significantly faster than in animals treated with empty PLGA conduits. Histological examinations also demonstrated increased axonal and Schwann cell regeneration within the reconstructed nerve gap in animals treated with conduit/PA constructs. These results indicate that PA nanofibers may represent a promising biomaterial for use in bioengineered peripheral nerve repair.

Gd(III)-labeled peptide nanofibers for reporting on biomaterial localization in vivo.

Bioactive supramolecular nanostructures are of great importance in regenerative medicine and the development of novel targeted therapies. In order to use supramolecular chemistry to design such nanostructures, it is extremely important to track their fate in vivo through the use of molecular imaging strategies. Peptide amphiphiles (PAs) are known to generate a wide array of supramolecular nanostructures, and there is extensive literature on their use in areas such as tissue regeneration and therapies for disease. We report here on a series of PA molecules based on the well-established ß-sheet amino acid sequence V3A3 conjugated to macrocyclic Gd(III) labels for magnetic resonance imaging (MRI). These conjugates were shown to form cylindrical supramolecular assemblies using cryogenic transmission electron microscopy and small-angle X-ray scattering. Using nuclear magnetic relaxation dispersion analysis, we observed that thermal annealing of the nanostructures led to a decrease in water exchange lifetime (τm) of hundreds of nanoseconds only for molecules that self-assemble into nanofibers of high aspect ratio. We interpret this decrease to indicate more solvent exposure to the paramagnetic moiety on annealing, resulting in faster water exchange within angstroms of the macrocycle. We hypothesize that faster water exchange in the nanofiber-forming PAs arises from the dehydration and increase in packing density on annealing. Two of the self-assembling conjugates were selected for imaging PAs after intramuscular injections of the PA C16V3A3E3-NH2 in the tibialis anterior muscle of a murine model. Needle tracts were clearly discernible with MRI at 4 days postinjection. This work establishes Gd(III) macrocycle-conjugated peptide amphiphiles as effective tracking agents for peptide amphiphile materials in vivo over the timescale of days.

Electrospinning bioactive supramolecular polymers from water.

Electrospinning is a high-throughput, low-cost technique for manufacturing long fibers from solution. Conventionally, this technique is used with covalent polymers with large molecular weights. We report here the electrospinning of functional peptide-based supramolecular polymers from water at very low concentrations (<4 wt %). Molecules with low molecular weights (<1 kDa) could be electrospun because they self-assembled into one-dimensional supramolecular polymers upon solvation and the critical parameters of viscosity, solution conductivity, and surface tension were optimized for this technique. The supramolecular structure of the electrospun fibers could ensure that certain residues, like bioepitopes, are displayed on the surface even after processing. This system provides an opportunity to electrospin bioactive supramolecular materials from water for biomedical applications.

Racial-ethnic differences in lacunar infarction in a multiethnic stroke population.

A higher incidence of lacunar infarction (LI) has been reported in nonwhite stroke populations. This study examined racial-ethnic differences in the clinical presentation and imaging findings of a racially-ethnically diverse population with acute LIs. Patients with acute LIs were identified over a 3-year period. Baseline clinical characteristics, vascular risk factors, and magnetic resonance imaging findings were analyzed. Comparisons were made between African Americans, Caribbean blacks, Caribbean Hispanics, and non-Hispanic whites. During the study period, 1036 patients with ischemic stroke were admitted, 194 of whom (25%) had a LI. The proportion of LI was the highest in Caribbean blacks (40%) and lowest in non-Hispanic whites (7%), with African Americans (25%) and Caribbean Hispanics (22%) showing a similar frequency. The mean patient age was 62 ± 12 years, and the study group was 55% male. Hypertension (92%) and dyslipidemia (74%) were the most frequent risk factors. The prevalence of hypertension was highest in African Americans and Caribbean blacks, whereas Caribbean Hispanics were more likely to smoke and have dyslipidemia. Despite similar vascular risk factors and a shared genealogy, the proportion of LI differed in African Americans and Caribbean blacks. Conversely, no difference in the prevalence of LI was seen in African Americans and Caribbean Hispanics, even though the 2 groups had differences in vascular risk factors. Our findings suggest that other determinants besides traditional vascular risk factors influence the risk of LI.

Association between variations in coagulation system genes and carotid plaque.

OBJECTIVE: Genetic variation in coagulation and fibrinolysis may affect the development of subclinical atherosclerosis modifying the risk of stroke and cardiovascular disease. However, data on the relationship between subclinical atherosclerosis and genes involved in the coagulation system are sparse. The objective of this study is to examine the association between single nucleotide polymorphisms (SNPs) in coagulation system genes and subclinical carotid plaque phenotypes. METHODS: From the Genetic Determinants of Subclinical Carotid Disease Study, 287 Dominicans were examined for carotid plaque presence, thickness, and surface irregularity by high-resolution B-mode carotid ultrasound. Logistic regression was used to test for association between 101 SNPs in 23 coagulation system genes and plaque phenotypes while controlling for age, sex, smoking, hypertension, dyslipidemia, and diabetes. Within gene haplotypes and interactions between genes were examined. A follow-up of SNPs in moderate to high (r(2)>0.25) linkage disequilibrium (LD) with those implicated in the discovery analysis (p ≤ 0.01) was performed in an independent sample of 301 Dominicans. RESULTS: The prevalence of carotid plaque (47% discovery; 46% follow-up) as well as the mean age (65 ± 8 discovery; 65 ± 9 follow-up) of the participants was similar in both datasets. Two genes (vWF and THBS1) were associated (p ≤ 0.01) with plaque size and surface irregularity. In follow-up, 5 SNPs in vWF were associated (p ≤ 0.05) with plaque size. SERPINE1 was an additional gene of interest in the haplotype and interaction analyses. CONCLUSIONS: Variation in the vWF, THBS1, and SERPINE1 gene may play an important role in the pathogenesis of atherosclerotic plaque.

Development of a mechanically tuneable 3D scaffold for vascular reconstruction.

Material compliance has been shown to be a predictor of vascular graft patency and as such is a critical parameter when designing new materials. Although ex vivo derived materials have been clinically successful in a number of applications their mechanical properties are a direct function of the original vessel and are not easily controllable. These investigations describe an approach to modulate the mechanical properties of an ex vivo derived scaffold by machining variable (discrete) wall thicknesses to control compliance. Human umbilical arteries (HUAs) were machine lathed directly from the umbilical cord at wall thicknesses of 250, 500, 750, and 1000 µm then decellularized using 1% sodium dodecyl sulfate. Compliance over physiological pressures, increased from 3.08 ± 1.84% to 11.47 ± 4.11% as direct function of each discrete vessel diameter. Radial stress strain analysis revealed primary and secondary failure points attributed to the discrete layers within the anisotropic scaffold. Maximum strength and suture retention were shown to increase with increasing wall thickness, by contrast stress failure decreased with increasing thickness due to increasing proportions of the mechanically weaker amorphous Wharton's jelly. Reseeded smooth muscle cells were shown to adhere, proliferate, and migrate from the scaffold surface showing the potential of the HUA as a mechanically "tunable" material with applications as an acellular implant or as a tissue engineered construct. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 100A:3189-3196, 2012.

Tubular hydrogels of circumferentially aligned nanofibers to encapsulate and orient vascular cells.

There is a great clinical need for tissue engineered blood vessels that could be used to replace or bypass damaged arteries. The success of such grafts will depend strongly on their ability to mimic the cellular and matrix organization found in native arteries, but currently available cell scaffolds such as electrospun fibers or hydrogels lack the ability to simultaneously encapsulate and align cells. Our laboratory has recently developed liquid crystalline solutions of peptide amphiphile nanofibers that form aligned domains at exceedingly low concentrations (<1 wt%), and can be trapped as gels with macroscopic alignment using low shear rates and ionic crosslinking. We describe here the use of these systems to fabricate tubes with macroscopic circumferential alignment and demonstrate their potential as arterial cell scaffolds. The nanofibers in these tubes were circumferentially aligned by applying small amounts of shear in a custom built flow chamber prior to gelation. Small angle X-ray scattering confirmed that the direction of nanofiber alignment was the same as the direction of shear flow. We also show the encapsulation of smooth muscle cells during the fabrication process without compromising cell viability. After two days in culture the encapsulated cells oriented their long axis in the direction of nanofiber alignment thus mimicking the circumferential alignment seen in native arteries. Cell density roughly doubled after 12 days demonstrating the scaffold's ability to facilitate necessary graft maturation. Since these nanofiber gels are composed of >99% water by weight, the cells have abundant room for proliferation and remodeling. In contrast to previously reported arterial cell scaffolds, this new material can encapsulate cells and direct cellular organization without the requirement of external stimuli or gel compaction.

Association of the sirtuin and mitochondrial uncoupling protein genes with carotid plaque.

OBJECTIVE: Sirtuins (SIRTs) and mitochondrial uncoupling proteins (UCPs) have been implicated in cardiovascular diseases through the control of reactive oxygen species production. This study sought to investigate the association between genetic variants in the SIRT and UCP genes and carotid plaque. METHODS: In a group of 1018 stroke-free subjects from the Northern Manhattan Study with high-definition carotid ultrasonography and genotyping, we investigated the associations of 85 single nucleotide polymorphisms (SNPs) in the 11 SIRT and UCP genes with the presence and number of carotid plaques, and evaluated interactions of SNPs with sex, smoking, diabetes and hypertension as well as interactions between SNPs significantly associated with carotid plaque. RESULTS: Overall, 60% of subjects had carotid plaques. After adjustment for demographic and vascular risk factors, T-carriers of the SIRT6 SNP rs107251 had an increased risk for carotid plaque (odds ratio, OR = 1.71, 95% CI = 1.23-2.37, Bonferroni-corrected p = 0.03) and for a number of plaques (rate ratio, RR = 1.31, 1.18-1.45, Bonferroni-corrected p = 1.4×10(-5)), whereas T-carriers of the UCP5 SNP rs5977238 had an decreased risk for carotid plaque (OR = 0.49, 95% CI = 0.32-0.74, Bonferroni-corrected p = 0.02) and plaque number (RR = 0.64, 95% CI = 0.52-0.78, Bonferroni-corrected p = 4.9×10(-4)). Some interactions with a nominal p≤0.01 were found between sex and SNPs in the UCP1 and UCP3 gene; between smoking, diabetes, hypertension and SNPs in UCP5 and SIRT5; and between SNPs in the UCP5 gene and the UCP1, SIRT1, SIRT3, SIRT5, and SIRT6 genes in association with plaque phenotypes. CONCLUSION: We observed significant associations between genetic variants in the SIRT6 and UCP5 genes and atherosclerotic plaque. We also found potential effect modifications by sex, smoking and vascular risk factors of the SIRT/UCP genes in the associations with atherosclerotic plaque. Further studies are needed to validate our observations.