Na+/H+ exchanger isoform 1 induced cardiomyocyte hypertrophy involves activation of p90 ribosomal S6 Kinase

Studies using pharmacological and genetic approaches have shown that increased activity/expression of the Na+/H+ exchanger isoform 1 (NHE1) play a critical role in the pathogenesis of cardiac hypertrophy. Despite the importance of NHE1 in cardiac hypertrophy, severe cerebrovascular side effects were associated with the use of NHE1 inhibitors when administered to patients with myocardial infarctions. p90 ribosomal S6 Kinase (RSK), a downstream regulator of the mitogen-activated protein kinase pathway, has also been implicated in cardiac hypertrophy. We hypothesized that RSK plays a role in the NHE1 induced cardiomyocyte hypertrophic response. Infection of H9c2 cardiomyoblasts with the active form of the NHE1 adenovirus induced hypertrophy and was associated with an increase in the phosphorylation of RSK (P<0.05). Parameters of hypertrophy such as cell area, protein content and atrial natriuretic mRNA expression were significantly reduced in H9c2 cardiomyoblasts infected with active NHE1 in the presence of dominant negative RSK (DN-RSK) (P<0.05). These results confirm that NHE1 lies upstream of RSK. Increased phosphorylation and activation of GATA4 at Ser261 was correlated with increased RSK phosphorylation. This increase was reversed upon inhibition of RSK or NHE1. These findings demonstrate for the first time that the NHE1 mediated hypertrophy is accounted for by increased activation and phosphorylation of RSK, which subsequently increased the phosphorylation of GATA4; eventually activating fetal gene transcriptional machinery.Qatar University Internal Grant (QUUG-CPH-CPH-11/12-1) and by the Undergraduate Research Experience Program (UREP11-027-3-005) provided by the Qatar National Research Fund, Doha, Qatar.Scopu

Long-Chain n-3 Fatty Acids Attenuate Oncogenic KRas-Driven Proliferation by Altering Plasma Membrane Nanoscale Proteolipid Composition

Ras signaling originates from transient nanoscale compartmentalized regions of the plasma membrane composed of specific proteins and lipids. The highly specific lipid composition of these nanodomains, termed nanoclusters, facilitates effector recruitment and therefore influences signal transduction. This suggests that Ras nanocluster proteolipid composition could represent a novel target for future chemoprevention interventions. There is evidence that consumption of fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) such as eicosapentaenoic acid (EPA, 20:5Δ5,8,11,14,17) and docosahexaenoic acid (DHA, 22:6Δ4,7,10,13,16,19) may reduce colon cancer risk in humans, yet the mechanism underlying this effect is unknown. Here, we demonstrate that dietary n-3 PUFA reduce the lateral segregation of cholesterol-dependent and -independent nanoclusters, suppressing phosphatidic acid-dependent oncogenic KRas effector interactions, via their physical incorporation into plasma membrane phospholipids. This results in attenuation of oncogenic Ras-driven colonic hyperproliferation in both Drosophila and murine models. These findings demonstrate the unique properties of dietary n-3 PUFA in the shaping of Ras nanoscale proteolipid complexes and support the emerging role of plasma membrane-targeted therapies. Significance: The influence of dietary long chain n-3 polyunsaturated fatty acids on plasma membrane protein nanoscale organization and KRas signaling supports development of plasma membrane-targeted therapies in colon cancer

Author Correction: Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation (Scientific Reports DOI: 10.1038/s41598-018-22819-3)

peer reviewe

Implication of LRP1 and ShcA in two cardiovascular diseases : atherosclerosis and heart failure

Les maladies cardiovasculaires sont la première cause de mortalité dans le monde. Une meilleure compréhension des mécanismes physiopathologiques est nécessaire. Dans ce travail de thèse nous nous sommes intéressés à deux pathologies cardiovasculaires : l’athérosclérose et l’insuffisance cardiaque. Récemment, nous avons identifié le récepteur LRP1 et la protéine adaptatrice ShcA comme étant deux protéines impliquées dans deux de ces pathologies cardiovasculaires. Nousavons montré que ShcA joue un rôle protecteur dans l’insuffisance cardiaque. Chez les souris déficientes en ShcA au niveau cardiaque, nous observons une cardiomyopathie caractérisée par une dilatation du ventricule gauche associée à une perte de la contractilité. Nous avons montré que ShcA est essentiel à l’organisation des sarcomères et ceci très tôt durant l’embryogenèse. Dans une deuxième partie nous avons montré qu’en l’absence de PPARgamma, LRP1 était nécessaire à la calcification vasculaire en activant la voie prochondrogénique de Wnt5a. Nous avons montré que PPARgamma protège de la calcification vasculaire en induisant l’expression de Sfrp2 qui agit comme un antagoniste de Wnt5a.Cardiovascular disease is the number one cause of death worldwide. A better understanding of the pathophysiological mechanisms is necessary. In this thesis we are focused on two cardiovascular diseases: atherosclerosis and heart failure. Recently, we identified the LRP1 receptor and the adapter protein ShcA as two proteins involved in two of these cardiovascular diseases. We have shown that ShcA exerts a protective role against heart failure. Mutant mice lacking ShcA in the heart exhibit a dilated cardiomyopathy with reduced cardiac contractility. Myocyte ultrastructure analysis shows that Shc A is essential to maintain sarcomeric intégrity in early embryonic heart development. in last part we have shown vascular calcification in the absence of PPARgamma requires expression of LRP1 in vascular smooth muscle cells. LRP1 promotes a Wnt5a-dependent prochondrogenic pathway. We show that PPARgamma protects against vascular calcification by inducing the expression of secreted frizzled-related protein-2 (Sfrp2, wich functions as a Wnt5a antagonist

Integrin-ECM interactions and membrane-associated Catalase cooperate to promote resilience of the Drosophila intestinal epithelium.

Balancing cellular demise and survival constitutes a key feature of resilience mechanisms that underlie the control of epithelial tissue damage. These resilience mechanisms often limit the burden of adaptive cellular stress responses to internal or external threats. We recently identified Diedel, a secreted protein/cytokine, as a potent antagonist of apoptosis-induced regulated cell death in the Drosophila intestinal midgut epithelium during aging. Here, we show that Diedel is a ligand for RGD-binding Integrins and is thus required for maintaining midgut epithelial cell attachment to the extracellular matrix (ECM)-derived basement membrane. Exploiting this function of Diedel, we uncovered a resilience mechanism of epithelial tissues, mediated by Integrin-ECM interactions, which shapes cell death spreading through the regulation of cell detachment and thus cell survival. Moreover, we found that resilient epithelial cells, enriched for Diedel-Integrin-ECM interactions, are characterized by membrane association of Catalase, thus preserving extracellular reactive oxygen species (ROS) balance to maintain epithelial integrity. Intracellular Catalase can relocalize to the extracellular membrane to limit cell death spreading and repair Integrin-ECM interactions induced by the amplification of extracellular ROS, which is a critical adaptive stress response. Membrane-associated Catalase, synergized with Integrin-ECM interactions, likely constitutes a resilience mechanism that helps balance cellular demise and survival within epithelial tissues

Implication de LRP1 et ShcA dans deux pathologies cardiovasculaires (l'arthérosclérose et l'insuffisance cardiaque)

Les maladies cardiovasculaires sont la première cause de mortalité dans le monde. Une meilleure compréhension des mécanismes physiopathologiques est nécessaire. Dans ce travail de thèse nous nous sommes intéressés à deux pathologies cardiovasculaires : l athérosclérose et l insuffisance cardiaque. Récemment, nous avons identifié le récepteur LRP1 et la protéine adaptatrice ShcA comme étant deux protéines impliquées dans deux de ces pathologies cardiovasculaires. Nousavons montré que ShcA joue un rôle protecteur dans l insuffisance cardiaque. Chez les souris déficientes en ShcA au niveau cardiaque, nous observons une cardiomyopathie caractérisée par une dilatation du ventricule gauche associée à une perte de la contractilité. Nous avons montré que ShcA est essentiel à l organisation des sarcomères et ceci très tôt durant l embryogenèse. Dans une deuxième partie nous avons montré qu en l absence de PPARgamma, LRP1 était nécessaire à la calcification vasculaire en activant la voie prochondrogénique de Wnt5a. Nous avons montré que PPARgamma protège de la calcification vasculaire en induisant l expression de Sfrp2 qui agit comme un antagoniste de Wnt5a.Cardiovascular disease is the number one cause of death worldwide. A better understanding of the pathophysiological mechanisms is necessary. In this thesis we are focused on two cardiovascular diseases: atherosclerosis and heart failure. Recently, we identified the LRP1 receptor and the adapter protein ShcA as two proteins involved in two of these cardiovascular diseases. We have shown that ShcA exerts a protective role against heart failure. Mutant mice lacking ShcA in the heart exhibit a dilated cardiomyopathy with reduced cardiac contractility. Myocyte ultrastructure analysis shows that Shc A is essential to maintain sarcomeric intégrity in early embryonic heart development. in last part we have shown vascular calcification in the absence of PPARgamma requires expression of LRP1 in vascular smooth muscle cells. LRP1 promotes a Wnt5a-dependent prochondrogenic pathway. We show that PPARgamma protects against vascular calcification by inducing the expression of secreted frizzled-related protein-2 (Sfrp2, wich functions as a Wnt5a antagonist.STRASBOURG-Bib.electronique 063 (674829902) / SudocSudocFranceF

Farm manure and bentonite clay amendments enhance the date palm morphology and yield

Date palm production contributes significantly to socio-economic development and food security in the dryland areas of Southern Tunisia. Soil degradation and nutrient depletion have dramatically increased in recent years. This is leading to a decline in date palm yields in these oases-based production systems. Locally derived bentonite clay has been identified as a new soil amendment to improve date morphological characteristics and date production. In this study, a 3-year field experimental study was carried out on 3-year-old Deglet Nour date palms growing in sandy soil of a Tunisian oasis (Fatnassa, Southern Tunisia). The study’s aim was to compare the effect of two amendment types: (i) sand (S) mixed with farm manure (M) and bentonite clay (B) (=BSM) and (ii) sand mixed with farm manure (SM) on the soil characteristics and morphological features of date palm. The results indicated that soil macro- and micronutrient contents were enhanced under BSM. Soil water retention in BSM also increased to 290 ± 0.3 mm m−1 compared to 70 ± 0.2 and 50 ± 0.5 mm m−1 for an untreated (no amendment) and SM treatment, respectively. The amelioration of morphological characteristics was observed for the canopy diameter reaching 226 ± 0.6 cm in BSM treatment compared to 172 ± 0.6 cm in untreated palm trees. The height of the palms increased by 69 ± 0.8 cm from 29 ± 0.1cm in the control treatment, and leaf number increased from 40 leaves palm−1 in BS to 60 leaves palm−1 in BSM treatment. The leaf mineral content was significantly been improved in the third year, and the leaf NPK contents were 220 ± 0.6 mg kg−1, 17 ± 0.1 mg kg−1, and 200 ± 0.04 mg kg−1, respectively, in BSM treatments. The effect of the farm manure and bentonite clay was noticeable for the yield production, and the SM and BSM treatments offered yields of 70 ± 0.9 kg palm−1 and 80 ± 0.5 kg palm−1, respectively. It could partly ameliorate the alternate year bearing phenomenon of the Deglet Nour date variety. We conclude that the joint application of farm manure and bentonite clay does represent a viable option to further improve the production and resilience of date palms in dryland areas

A virus-acquired host cytokine controls systemic aging by antagonizing apoptosis

<div><p>Aging is characterized by degeneration of unique tissues. However, dissecting the interconnectedness of tissue aging remains a challenge. Here, we employ a muscle-specific DNA damage model in <i>Drosophila</i> to reveal secreted factors that influence systemic aging in distal tissues. Utilizing this model, we uncovered a cytokine—Diedel—that, when secreted from muscle or adipose, can attenuate age-related intestinal tissue degeneration by promoting proliferative homeostasis of stem cells. Diedel is both necessary and sufficient to limit tissue degeneration and regulate lifespan. Secreted homologs of Diedel are also found in viruses, having been acquired from host genomes. Focusing on potential mechanistic overlap between cellular aging and viral-host cell interactions, we found that Diedel is an inhibitor of apoptosis and can act as a systemic rheostat to modulate cell death during aging. These results highlight a key role for secreted antagonists of apoptosis in the systemic coordination of tissue aging.</p></div

NHE1 induces phosphorylation and activation of RSK which would result in GATA4 phosphorylation.

<p>Leading to activation of transcription machinery and modulation of the hypertrophic pathway. Inhibition of RSK attenuates the NHE1 induced cardiomyocyte hypertrophic response.</p