Circulation research
-
Circulation research · Jul 2010
Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo.
Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for the majority of cases of heritable pulmonary arterial hypertension (PAH). Mutations lead to reduced Smad1/5-driven expression of inhibitor of DNA binding protein 1 (Id1) and loss of the growth suppressive effects of BMPs. The impact of existing PAH therapies on BMP signaling is lacking. ⋯ Prostacyclin analogues enhance Id1 expression in vitro and in vivo and restore deficient BMP signaling in BMPR-II mutant PASMCs.
-
Circulation research · Jun 2010
Role of afadin in vascular endothelial growth factor- and sphingosine 1-phosphate-induced angiogenesis.
Angiogenesis contributes to physiological and pathological conditions, including atherosclerosis. The Rap1 small G protein regulates vascular integrity and angiogenesis. However, little is known about the effectors of Rap1 involved in angiogenesis. It is not known whether afadin, an adherens junction protein that connects immunoglobulin-like adhesion molecule nectins to the actin cytoskeleton and binds activated Rap1, plays a role in angiogenesis. ⋯ These results demonstrate a novel molecular mechanism by which Rap1 and afadin regulate the VEGF- and S1P-induced angiogenesis.
-
Circulation research · Apr 2010
Case ReportsTrafficking defects and gating abnormalities of a novel SCN5A mutation question gene-specific therapy in long QT syndrome type 3.
Sodium channel blockers are used as gene-specific treatments in long-QT syndrome type 3, which is caused by mutations in the sodium channel gene (SCN5A). Response to treatment is influenced by biophysical properties of mutations. ⋯ Sodium channel blockers are largely used to shorten QT intervals in carriers of SCN5A mutations. We provided evidence that these agents may facilitate trafficking of mutant proteins, thus exacerbating QT prolongation. These data suggest that caution should be used when recommending this class of drugs to carriers of mutations with undefined electrophysiological properties.
-
Circulation research · Apr 2010
Lung endothelial dysfunction in congestive heart failure: role of impaired Ca2+ signaling and cytoskeletal reorganization.
Congestive heart failure (CHF) frequently results in remodeling and increased tone of pulmonary resistance vessels. This adaptive response, which aggravates pulmonary hypertension and thus, promotes right ventricular failure, has been attributed to lung endothelial dysfunction. ⋯ Our findings characterize a unique scenario of endothelial dysfunction in CHF that is caused by a singular impairment of [Ca(2+)](i) signaling, and identify cytoskeletal reorganization as a major regulator of endothelial signaling and function.
-
Circulation research · Feb 2010
Phospholamban ablation rescues sarcoplasmic reticulum Ca(2+) handling but exacerbates cardiac dysfunction in CaMKIIdelta(C) transgenic mice.
We previously showed that transgenic mice expressing Ca(2+)/calmodulin-dependent protein kinase II delta(C) (CaMKII-TG) develop dilated cardiomyopathy associated with increased ryanodine receptors (RyR2) phosphorylation, enhanced sarcoplasmic reticulum (SR) Ca(2+) leak and lowering of SR Ca(2+) load. We hypothesized that phospholamban (PLN) ablation would restore SR Ca(2+) load and prevent the decreased ventricular contractility, dilation and mortality seen in CaMKII-TG. ⋯ Normalizing cardiomyocyte SR Ca(2+) loading in the face of elevated CaMKII and RyR2 phosphorylation leads to enhanced SR Ca(2+) leak and mitochondrial Ca(2+) elevation, associated with exacerbated cell death, heart failure and mortality.