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Angioplasty and stenting is the primary treatment for flow-limiting atherosclerosis; however, this strategy is limited by pathological vascular remodeling. Using a systems approach, we identified a role for the network hub gene glutathione peroxidase-1 (GPX1) in pathological remodeling following human blood vessel stenting. Constitutive deletion of Gpx1 in atherosclerotic mice recapitulated this phenotype of increased vascular smooth muscle cell (VSMC) proliferation and plaque formation. In an independent patient cohort, gene variant pair analysis identified an interaction of GPX1 with the orphan protooncogene receptor tyrosine kinase ROS1. A meta-analysis of the only genome-wide association studies of human neointima-induced in-stent stenosis confirmed the association of the ROS1 variant with pathological remodeling. Decreased GPX1 expression in atherosclerotic mice led to reductive stress via a time-dependent increase in glutathione, corresponding to phosphorylation of the ROS1 kinase activation site Y2274. Loss of GPX1 function was associated with both oxidative and reductive stress, the latter driving ROS1 activity via s-glutathiolation of critical residues of the ROS1 tyrosine phosphatase SHP-2. ROS1 inhibition with crizotinib and deglutathiolation of SHP-2 abolished GPX1-mediated increases in VSMC proliferation while leaving endothelialization intact. Our results indicate that GPX1-dependent alterations in oxido- reductive stress promote ROS1 activation and mediate vascular remodeling., Introduction Balloon angioplasty and stenting (BAS) is the most commonly performed method of revascularization for flow-limiting atherosclerosis, with over 1.5 million procedures performed annually in the United States (1). The [...]

Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice donor site, [...]

Vascular proliferative diseases are characterized by VSMC proliferation and migration. Kinase interacting with stathmin (KIS) targets 2 key regulators of cell proliferation and migration, the cyclin-dependent kinase inhibitor [p27.sup.Kip1] and the microtubule-destabilizing protein stathmin. Phosphorylation of [p27.sup.Kip1] by KIS leads to cell-cycle progression, whereas the target sequence and the physiological relevance of KIS-mediated stathmin phosphorylation in VSMCs are unknown. Here we demonstrated that vascular wound repair in KIS-/- mice resulted in accelerated formation of neointima, which is composed predominantly of VSMCs. Deletion of KIS increased VSMC migratory activity and cytoplasmic tubulin destabilizing activity, but abolished VSMC proliferation through the delayed nuclear export and degradation of [p27.sup.Kip1]. This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of KIS-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation. Downregulation of stathmin in KIS-/- VSMCs fully restored the phenotype, and stathmin-deficient mice demonstrated reduced lesion formation in response to vascular injury. These data suggest that KIS protects against excessive neointima formation by opposing stathmin-mediated VSMC migration and that VSMC migration represents a major mechanism of vascular wound repair, constituting a relevant target and mechanism for therapeutic interventions., Introduction Vascular remodeling and wound repair constitute complex mechanisms aimed at restoration of vessel integrity and vessel function. This involves cells within the vessel wall, predominantly VSMCs, and the recruitment [...]

A study to examine cases of children suffering from Hutchinson-Guilford progeria syndrome, a degenerative disease and lamin A being the gene carrying it is conducted. Results indicate that the lamin A gene is vital to help develop the understanding of ageing.

Results of a study conducted to establish whether patients were affected by a conflict of interests including financial indicated that for most it did not matter. It is very important to preserve faith and trust in research.

Gene mutations involved in cardiovascular disease are described. Topics include mutations that affect blood pressure and cholesterol levels, coronary artery disease, hypertension, thrombosis and hemostasis, hypertrophic cardiomyopathy, cardiac arrhythmias, gene polymorphisms, and gene-expression profiling. There are no genetic tests for cardiovascular disease.

Heme oxygenase (HO-1, encoded by Hmox1) is an inducible protein activated in systemic inflammatory conditions by oxidant stress. Vascular injury is characterized by a local reparative process with inflammatory components, indicating a potential protective role for HO-1 in arterial wound repair. Here we report that HO-1 directly reduces vasoconstriction and inhibits cell proliferation during vascular injury. Expression of HO-1 in arteries stimulated vascular relaxation, mediated by guanylate cyclase and cGMP, independent of nitric oxide. The unexpected effects of HO-1 on vascular smooth muscle cell growth were mediated by cell-cycle arrest involving p21[sup.Cip1]. HO-1 reduced the proliferative response to vascular injury in vivo; expression of HO-1 in pig arteries inhibited lesion formation and Hmox1[sup.-/-] mice produced hyperplastic arteries compared with controls. Induction of the HO-1 pathway moderates the severity of vascular injury by at least two adaptive mechanisms independent of nitric oxide, and is a potential therapeutic target for diseases of the vasculature., Author(s): Henricus J. Duckers [1]; Manfred Boehm [1]; Andrea L. True [1]; Shaw-Fang Yet [4]; Hong San [1]; James L. Park [3]; R. Clinton Webb [3]; Mu-En Lee [4]; Gary [...]