CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity.

The chromatin-remodeling enzyme CHD4 maintains vascular integrity at mid-gestation; however, it is unknown whether this enzyme contributes to later blood vessel or lymphatic vessel development. Here, we addressed this issue in mice harboring a deletion of Chd4 specifically in cells that express lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), which include lymphatic endothelial cells (LECs) and liver sinusoidal endothelial cells. Chd4 mutant embryos died before birth and exhibited severe edema, blood-filled lymphatics, and liver hemorrhage.

The NuRD chromatin-remodeling enzyme CHD4 promotes embryonic vascular integrity by transcriptionally regulating extracellular matrix proteolysis.

The extracellular matrix (ECM) supports vascular integrity during embryonic development. Proteolytic degradation of ECM components is required for angiogenesis, but excessive ECM proteolysis causes blood vessel fragility and hemorrhage. Little is understood about how ECM proteolysis is transcriptionally regulated during embryonic vascular development.

BRG1 promotes COUP-TFII expression and venous specification during embryonic vascular development.

Arteries and veins acquire distinct molecular identities prior to the onset of embryonic blood circulation, and their specification is crucial for vascular development. The transcription factor COUP-TFII currently functions at the top of a signaling pathway governing venous fate. It promotes venous identity by inhibiting Notch signaling and subsequent arterialization of endothelial cells, yet nothing is known about what regulates COUP-TFII expression in veins.

Chromatin-remodeling complex specificity and embryonic vascular development.

Vascular development is a dynamic process that relies on the coordinated expression of numerous genes, but the factors that regulate gene expression during blood vessel development are not well defined. ATP-dependent chromatin-remodeling complexes are gaining attention for their specific temporal and spatial effects on gene expression during vascular development. Genetic mutations in chromatin-remodeling complex subunits are revealing roles for the complexes in vascular signaling pathways at discrete developmental time points.

The chromatin-remodeling enzymes BRG1 and CHD4 antagonistically regulate vascular Wnt signaling.

Canonical Wnt signaling plays an important role in embryonic and postnatal blood vessel development. We previously reported that the chromatin-remodeling enzyme BRG1 promotes vascular Wnt signaling. Vascular deletion of Brg1 results in aberrant yolk sac blood vessel morphology, which is rescued by pharmacological stimulation of Wnt signaling with lithium chloride (LiCl).

Community Outreach and Cardiovascular Health (COACH) Trial: a randomized, controlled trial of nurse practitioner/community health worker cardiovascular disease risk reduction in urban community health centers.

Background: Despite well-publicized guidelines on the appropriate management of cardiovascular disease and type 2 diabetes, the implementation of risk-reducing practices remains poor. This report describes the results of a randomized, controlled clinical trial evaluating the effectiveness of a comprehensive program of cardiovascular disease risk reduction delivered by nurse practitioner /community health worker (NP/CHW) teams versus enhanced usual care (EUC) to improve lipids, blood pressure, glycated hemoglobin (HbA1c), and patient perceptions of the quality of their chronic illness care in patients in urban community health centers.

Methods And Results: A total of 525 patients with documented cardiovascular disease, type 2 diabetes, hypercholesterolemia, or hypertension and levels of LDL cholesterol, blood pressure, or HbA1c that exceeded goals established by national guidelines were randomly assigned to NP/CHW (n=261) or EUC (n=264) groups.

The chromatin-remodeling enzyme BRG1 modulates vascular Wnt signaling at two levels.

The ATP-dependent chromatin-remodeling enzyme brahma-related gene 1 (BRG1) regulates transcription of specific target genes during embryonic and postnatal development. Deletion of Brg1 from embryonic blood vessels results in yolk sac vascular remodeling defects. We now report that misregulation of the canonical Wnt signaling pathway underlies many Brg1 mutant vascular phenotypes.

Immunohistochemical analysis of oxidative stress and DNA repair proteins in normal mammary and breast cancer tissues.

Background: During the course of normal cellular metabolism, oxygen is consumed and reactive oxygen species (ROS) are produced. If not effectively dissipated, ROS can accumulate and damage resident proteins, lipids, and DNA. Enzymes involved in redox regulation and DNA repair dissipate ROS and repair the resulting damage in order to preserve a functional cellular environment.

Long-range transcriptional control of progesterone receptor gene expression.

Estrogen receptor alpha (ERalpha) binds to specific target DNA sequences, estrogen response elements (EREs), to regulate estrogen-responsive gene expression. The progesterone receptor (PR) gene has been used extensively as a marker of estrogen responsiveness. Although we previously identified cis elements within 1 kb of the PR-B transcription start site that are associated with ERalpha and help to confer estrogen responsiveness, the identification of ERalpha binding sites far removed from the transcription start site suggested that long-range regulation of this gene may occur.

Apurinic/apyrimidinic endonuclease 1 alters estrogen receptor activity and estrogen-responsive gene expression.

Apurinic/apyrimidinic endonuclease 1 or redox factor-1 (Ape1/Ref-1) is a pleiotropic cellular protein involved in DNA repair and, through its redox activity, enhances the binding of a select group of transcription factors to their cognate recognition sequences in DNA. Thus, we were intrigued when we identified Ape1/Ref-1 and a number of DNA repair and oxidative stress proteins in a complex associated with the DNA-bound estrogen receptor alpha (ERalpha). Because Ape1/Ref-1 interacts with a number of transcription factors and influences their activity, we determined whether it might also influence ERalpha activity.

Using RNA interference to study protein function.

RNA interference can be extremely useful in determining the function of an endogenously-expressed protein in its normal cellular environment. In this chapter, we describe a method that uses small interfering RNA (siRNA) to knock down mRNA and protein expression in cultured cells so that the effect of a putative regulatory protein on gene expression can be delineated. Methods of assessing the effectiveness of the siRNA procedure using real time quantitative PCR and Western analysis are also included.

Interaction of the tumor metastasis suppressor nonmetastatic protein 23 homologue H1 and estrogen receptor alpha alters estrogen-responsive gene expression.

Metastasis of cancer cells from the primary tumor is associated with poor prognosis and decreased overall survival. One protein implicated in inhibiting metastasis is the tumor metastasis suppressor nonmetastatic protein 23 homologue 1 (NM23-H1). NM23-H1 is a multifunctional protein, which, in addition to limiting metastasis, has DNase and histidine protein kinase activities.

Use of the ABC care bundle to standardize guideline implementation in a cardiac surgical population: a pilot study.

A cardiac surgical progressive care unit implemented the ABC's of Cardiovascular Risk Reduction Care Bundle to determine whether the use of a packaged approach to medication prescription and lifestyle counseling would improve adherence to secondary risk-reduction guidelines in postcoronary artery bypass graft patients. A pilot study was carried out to assess changes in adherence to guideline recommendations post-Care Bundle implementation. Findings support using a systematic strategy to improve guideline adherence in this population.

Recruitment of African American and white postmenopausal women into clinical trials: the beneficial effects of soy trial experience.

Objective: To describe the strategies and costs associated with recruiting both African American and White postmenopausal women into a randomized controlled trial.

Design: The Beneficial Effects of Soy Trial (BEST) was a randomized, controlled trial designed to determine the effects of a dietary soy supplement on lipoproteins, lipoprotein subclasses, and menopausal symptoms in African American and White postmenopausal women. The goal was to have > or = 80 African American and > or = 80 White women complete the study.

Effect of soy protein-containing isoflavones on lipoproteins in postmenopausal women.

Objective: Some clinical trials have demonstrated a beneficial effect of dietary soy protein on improving lipoproteins. Research also has documented that serum lipoproteins and some lipoprotein subclasses are altered as a consequence of menopause, resulting in a more atherogenic lipid profile. The purpose of this study was to determine the effects of isolated soy protein-containing isoflavones on lipoproteins and lipoprotein subclasses in both African American and white postmenopausal women with borderline to moderate low-density lipoprotein cholesterol elevations.

A novel estrogen receptor alpha-associated protein alters receptor-deoxyribonucleic acid interactions and represses receptor-mediated transcription.

Estrogen receptor alpha (ER alpha) serves as a ligand-activated transcription factor, turning on transcription of estrogen-responsive genes in target cells. Numerous regulatory proteins interact with the receptor to influence ER alpha-mediated transactivation. In this study, we have identified pp32, which interacts with the DNA binding domain of ER alpha when the receptor is free, but not when it is bound to an estrogen response element.