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Articles by J. A. Epstein
Total Records ( 4 ) for J. A. Epstein
  J Xu , F. A Ismat , T Wang , M. M Lu , N Antonucci and J. A. Epstein

Rationale: Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with a broad array of clinical manifestations, including benign and malignant tumors, and characteristic cutaneous findings. NF1 patients also have an increased incidence of cardiovascular diseases, including obstructive vascular disorders and hypertension. The disease gene, NF1, encodes neurofibromin, a ubiquitously expressed protein that acts, in part, as a Ras-GAP (GTP-ase activating protein), downregulating the activity of activated Ras protooncogenes. In animal models, endothelial and smooth muscle expression of the disease gene is critical for normal heart development and the prevention of vascular disease, respectively.

Objective: To determine the role of NF1 in the postnatal and adult heart.

Methods and Results: We generated mice with homozygous loss of the murine homolog Nf1 in myocardium (Nf1mKO) and evaluated their hearts for biochemical, structural, and functional changes. Nf1mKO mice have normal embryonic cardiovascular development but have marked cardiac hypertrophy, progressive cardiomyopathy, and fibrosis in the adult. Hyperactivation of Ras and downstream pathways are seen in the heart with the loss of Nf1, along with activation of a fetal gene program.

Conclusions: This report describes a critical role of Nf1 in the regulation of cardiac growth and function. Activation of pathways known to be involved in cardiac hypertrophy and dysfunction are seen with the loss of myocardial neurofibromin.

  W Zhu , C. M Trivedi , D Zhou , L Yuan , M. M Lu and J. A. Epstein

Rationale: Cardiac hypertrophy occurs in response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway has previously been strongly associated with hypertrophic signaling in the heart, and with the control of cell size in multiple contexts. This pathway is tightly regulated by many factors, including a host of kinases and phosphatases that function at multiple steps in the signaling cascade. For example, the PTEN (phosphatase and tensin homolog) tumor suppressor protein is a phosphoinositide 3-phosphatase that, by metabolizing phosphatidylinositol 3,4,5-trisphosphate (PtdIns[3,4,5]P3, PIP3), acts in direct antagonism to growth factor–stimulated PI3K. Inhibition of PTEN leads to cardiomyocyte hypertrophy. Another polyphoinositide phosphatase, inositol polyphosphate-5-phosphatase F (Inpp5f) has recently been implicated in regulation of cardiac hypertrophy. Like PTEN, this phosphatase can degrade PtdIns(3,4,5)P3 and thus modulates the PI3K/Akt pathway.

Objective: To characterize the role of Inpp5f in regulating cardiac hypertrophy.

Methods and Results: We generated homozygous Inpp5f knockout mice and cardiac specific Inpp5f overexpression transgenic mice. We evaluated their hearts for biochemical, structural and functional changes. Inpp5f knockout mice have augmented hypertrophy and reactivation of the fetal gene program in response to stress when compared to wild-type littermates. Furthermore, cardiac overexpression of Inpp5f in transgenic mice reduces hypertrophic responsiveness.

Conclusions: Our results suggest that Inpp5f is a functionally important endogenous modulator of cardiac myocyte size and of the cardiac response to stress.

  K Degenhardt , A. C Wright , D Horng , A Padmanabhan and J. A. Epstein

Background— Microcomputed tomography (micro-CT) has been used extensively in research to generate high-resolution 3D images of calcified tissues in small animals nondestructively. It has been especially useful for the characterization of skeletal mutations but limited in its utility for the analysis of soft tissue such as the cardiovascular system. Visualization of the cardiovascular system has been largely restricted to structures that can be filled with radiopaque intravascular contrast agents in adult animals. Recent ex vivo studies using osmium tetroxide, iodinated contrast agents, inorganic iodine, and phosphotungstic acid have demonstrated the ability to stain soft tissues differentially, allowing for high intertissue contrast in micro-CT images. In the present study, we demonstrate the application of this technology for visualization of cardiovascular structures in developing mouse embryos using Lugol solution (aqueous potassium iodide plus iodine).

Methods and Results— We show the optimization of this method to obtain ex vivo micro-CT images of embryonic and neonatal mice with excellent soft-tissue contrast. We demonstrate the utility of this method to visualize key structures during cardiovascular development at various stages of embryogenesis. Our method benefits from the ease of sample preparation, low toxicity, and low cost. Furthermore, we show how multiple cardiac defects can be demonstrated by micro-CT in a single specimen with a known genetic lesion. Indeed, a previously undescribed cardiac venous abnormality is revealed in a PlexinD1 mutant mouse.

Conclusions— Micro-CT of iodine-stained tissue is a valuable technique for the characterization of cardiovascular development and defects in mouse models of congenital heart disease.

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