Sarcomeric genes involved in reverse remodeling of the heart during left ventricular assist device support.

Background: Left ventricular assist devices (LVADs) implanted in patients with severe congestive heart failure (CHF) as a bridge to transplantation have been shown to reverse chamber enlargement, regress cellular hypertrophy, and increase contractility. The purpose of this study was to gain a better understanding of the molecular changes associated with increased contractility after LVAD support.

Methods: We took tissue sections from the left ventricular apex of 12 patients with CHF who were undergoing LVAD insertion (pre-LVAD) and from the LV free wall of those same patients before transplantation (post-LVAD).

HRT1 modulates vascular smooth muscle cell proliferation and apoptosis.

The Notch signaling pathway plays vital roles in vascular development and homeostasis. However, the functional role of HRT1, a primary downstream effector of Notch signaling in VSMC, is poorly characterized. In the present study, we postulated that HRT1 plays fundamental roles in modulating VSMC fate.

DNA microarray profiling to identify angiotensin-responsive genes in vascular smooth muscle cells: potential mediators of vascular disease.

Angiotensin II (Ang II) induces changes in vessel structure by its capacity to activate genes that are coupled to signaling pathways such as extracellular signal-regulated kinase (ERK), p38, and phosphatidylinositol 3-kinase (PI3K). Using a DNA microarray containing 5088 genes and expressed sequence tags, we initially established a database of replicated experiments (n=4) to define the variances in mRNA expression in response to Ang II versus vehicle treatment. We observed a wide range of values for the coefficients of variation in a gene-specific manner.

Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation.

The Notch family of receptors and ligands plays an important role in cell fate determination, vasculogenesis, and organogenesis. Mutations of the Notch-3 receptor result in an arteriopathy that predisposes to early-onset stroke. However, the functional role of the Notch signaling pathway in adult vascular smooth muscle cells (VSMCs) is poorly characterized.

Coordinate Notch3-hairy-related transcription factor pathway regulation in response to arterial injury. Mediator role of platelet-derived growth factor and ERK.

The Notch family of receptors and downstream effectors plays a critical role in cell fate determination during vascular ontogeny. Moreover, the human cerebral autosomal dominant artriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome of premature stroke and dementia is a heritable arteriopathy with alterations in vascular smooth muscle cells (VSMCs) resulting from mutations within Notch3. However, the expression and regulation of the Notch and hairy-related transcription factor (HRT) pathway in adult VSMCs in vitro and in vivo remain poorly characterized.

Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis.

Mutations in the Notch3 receptor result in the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy (CADASIL) syndrome, a heritable arteriopathy predisposing to early onset stroke. Based upon clinical evidence that CADASIL arteriopathy results in degeneration and loss of vascular smooth muscle cells (VSMC) from the arterial wall, we postulated that Notch3 signaling is a critical determinant of VSMC survival. We initially established that both transient and constitutive Notch3 signaling promoted VSMC survival in response to the proapoptotic Fas ligand (FasL).