R ight ventricular (RV) function is a major determinant of functional capacity and survival in pulmonary arterial hypertension (PAH) and other types of pulmonary hypertension.1 Although afterload is a prominent determinant for RV systolic function in PAH, there remains significant variability between patients with PAH in the ability of the RV to adapt to pressure overload and pulmonary resistance.2,3 The mechanisms accounting for this variability in RV adaptability to increased pulmonary load and for the transition to RV failure remain elusive. Despite the tremendous attention that left ventricular (LV) failure has received, RV failure has remained understudied at both the preclinical and clinical levels. 3 As a result, RV failure has emerged as an important research priority in the cardiopulmonary research field. Clinical Perspective on p 943Magnetic resonance imaging performed in patients with PAH has shown that the hypertrophied RV is ischemic 5 andBackground-Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH. Methods and Results-We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription-polymerase chain reaction; P<0.01) and capillary density (CD31 + immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals. Conclusions-RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH. Key Words: hypertension, pulmonary ◼ microRNAs ◼ microvessels ◼ pulmonary heart disease ◼ right ventricular failure © 2015 American Heart Assoc...

Islet-specific glucose-6-phosphatase (G6Pase) catalytic subunit-related protein (IGRP) is a homolog of the catalytic subunit of G6Pase, the enzyme that catalyzes the terminal step of the gluconeogenic pathway. Its catalytic activity, however, has not been defined. Since IGRP gene expression is restricted to islets, this suggests a possible role in the regulation of islet metabolism and, hence, insulin secretion induced by metabolites. We report here a comparative analysis of the human, mouse, and rat IGRP genes. These studies aimed to identify conserved sequences that may be critical for IGRP function and that specify its restricted tissue distribution. The single copy human IGRP gene has five exons of similar length and coding sequence to the mouse IGRP gene and is located on human chromosome 2q28 -32 adjacent to the myosin heavy chain 1B gene. In contrast, the rat IGRP gene does not appear to encode a protein as a result of a series of deletions and insertions in the coding sequence. Moreover, rat IGRP mRNA, unlike mouse and human IGRP mRNA, is not expressed in islets or islet-derived cell lines, an observation that was traced by fusion gene analysis to a mutation of the TATA box motif in the mouse/human IGRP promoters to TGTA in the rat sequence. The results provide a framework for the further analysis of the molecular basis for the tissuerestricted expression of the IGRP gene and the identification of key amino acid sequences that determine its biological activity.

Aims/hypothesis An immunohistochemical and genomic analysis of human pancreatic development from 9-23 weeks of fetal age was undertaken to provide a comparative analysis of human and murine islet development. Methods Human fetal pancreases obtained at gestational ages 9-23 weeks were processed in parallel for immunohistochemistry and gene expression profiling by Affymetrix microarrays.