ABSTRACT: Cardiomyocyte Soluble Guanylyl Cyclase is Necessary for Estrogen Cardioprotection Against Capillary Rarefaction in Right Ventricular Pressure-Overload Remodeling
Project description:It is unclear why preterm birth increases risk of cardiovascular disease later in life. Studies in mice indicate excess oxygen used to treat preterm infants causes pulmonary hypertension, cardiac failure, and shortens lifespan. We previously reported neonatal hyperoxia causes pulmonary hypertension in aged mice as defined pathologically by pulmonary capillary rarefaction, dilation of pulmonary arterioles and veins, right ventricular hypertrophy, and reduced lifespan. Here, affymetrix gene arrays were used to identify early transcriptional changes in lungs of young adult mice exposed to room air or 100% oxygen between postnatal days 0-4.
Project description:The aberrant activation of the ERG oncogenic pathway due to TMPRSS2-ERG gene fusions is the major driver of prostate cancer initiation and progression. We identified the alpha1 and beta1 subunits of soluble guanylyl cyclase (GUCY1A1, GUCY1B1) as major ERG-regulated genes in prostate cancer cells. Soluble guanylyl cyclase (sGC) is the major mediator of nitric oxide signaling in cells that, upon nitric oxide binding, catalyzes the synthesis of cGMP and subsequently activates PKG. We showed in ERG-positive PCa cells (VCaP) that cGMP synthesis was significantly elevated by ERG, leading to increased PKG activity and cell proliferation. To further understand the functions of sGC-cGMP pathway in prostate cancer cells, we performed RNA-seq analyses in VCaP cells to identify genes that are regulated by sGC.
Project description:Genomic and behavioral investigations were performed to determine the effects of a mutation in a Drosophila soluble guanylyl cyclase gene. A mutant DGCalpha1[3] third chromosome was crossed into a natural rover (for[R]) or natural sitter (for[s]) genetic background. (See Osborne et al. 1997; PMID: 9242616.) First instar larvae were collected and grown on 60mm Petri plates containing 10 mL of food until mid-third instar. (Approximate density was 3 animals per mL food). Larvae were collected and washed quickly with distilled water and were flash frozen in liquid nitrogen. Co-reared larvae were tested for behavioural effects. Four independent collections were made for each of the two conditions (Rover_DGCalpha1[3] or sitter_DGCalpha1[3]). Keywords = Drosophila Keywords = foraging Keywords = behavior Keywords = cGMP Keywords = guanylyl cyclase Keywords = genetic background
Project description:Genomic and behavioral investigations were performed to determine the effects of a mutation in a Drosophila soluble guanylyl cyclase gene. A mutant DGCalpha1[3] third chromosome was crossed into a natural rover (for[R]) or natural sitter (for[s]) genetic background. (See Osborne et al. 1997; PMID: 9242616.) First instar larvae were collected and grown on 60mm Petri plates containing 10 mL of food until mid-third instar. (Approximate density was 3 animals per mL food). Larvae were collected and washed quickly with distilled water and were flash frozen in liquid nitrogen. Co-reared larvae were tested for behavioural effects. Four independent collections were made for each of the two conditions (Rover_DGCalpha1[3] or sitter_DGCalpha1[3]). Keywords = Drosophila Keywords = foraging Keywords = behavior Keywords = cGMP Keywords = guanylyl cyclase Keywords = genetic background Keywords: other
Project description:It is unclear why preterm birth increases risk of cardiovascular disease later in life. Studies in mice indicate excess oxygen typically used to treat preterm infants causes pulmonary hypertension, cardiac failure, and shortens lifespan. We previously reported neonatal hyperoxia causes pulmonary hypertension in aged mice as defined pathologically by pulmonary capillary rarefaction, dilation of pulmonary arterioles and veins, right ventricular hypertrophy, and reduced lifespan. These changes were preceded by a pronounced growth inhibition of cardiomyocytes lining the pulmonary vein and extending into the left atria, resulting in diastolic heart failure as the mice aged. To identify transcriptional changes by which hyperoxia suppresses proliferation of these cardiomyocytes, newborn mice were exposed to room air or 100% oxygen between birth and postnatal day 4. RNA was then isolated from atria of 3 room air and 4 hyperoxia-exposed mice and used to probe Affymetrix mouse array 430 versus 2.0
Project description:Dipeptidyl peptidase-4 (Dpp4) inhibitors are used worldwide to combat diabetes, however, their roles in cardiovascular disorders are yet to be defined. Here we show that a DPP4 inhibitor, linagliptin, contributes for the suppression of capillary rarefaction in cardiac tissues of dietary obese mice model. Imposing a high fat diet into mice induced capillary rarefaction and cardiac dysfunction. These pathologies associated with high DPP4 level in circulation, and the administration of linagliptin into dietary obese mice suppressed the development of capillary rarefaction and ameliorated cardiac dysfunction. Early growth response protein 1 (EGR1), known as an angiogenic transcription factor, is significantly reduced in the cardiac tissue upon metabolic stress, and this suppression was inhibited by the administration of linagliptin.
Project description:To investigate the transplantation of human induced pluripotent stem cell-derived cardiac lineage-cells into the heart of rhesus macaques with a surgical model of right ventricular pressure overload.