Crosstalk between SUMOylated PPARγ1 and FOXO1 Exerts a Positive-feedback Effect on Vascular Endothelial Insulin Resistance

Background: PPARγ and FOXO1 are key regulators of transcription factors that mediate insulin sensitivity. We previously showed that a small ubiquitin-related modifier of PPARγ1 at K77 (SUMOylation) favors endothelial insulin resistance (IR) induced by high-fat/high-glucose (HF/HG) administration. However, whether and how the crosstalk between SUMOylated PPARγ1 and FOXO1 mediates the development of IR remains unclear. Here, we place emphasis on elucidating how PPARγ1-K77 SUMOylation interacts with FOXO1 and participates in the development of endothelial IR.Methods: Adenovirus or adeno-associated virus carrying a truncated PPARγ1 containing AF1 and DBD domains fused with SUMO-1 (PPARγ1[1-182 aa]-SUMO-1 fusion protein) was utilized to simulate PPARγ1-K77 SUMOylation. Furthermore, we carried out PPARγ1-K77 SUMOylation imitating-IR and worsening-IR experiments in vitro and in vivo. The vascular diastolic function and levels of p-IKK, IKK, p-PI3K, PI3K, p-Akt, Akt, p-eNOS, and eNOS were measured. To elucidate the underlying mechanism, the interaction of PPARγ1-K77 SUMOylation and FOXO1 was examined by co-immunoprecipitation. The recruitment of PPARγ1 or FOXO1 to PPRE was analyzed by chromatin immunoprecipitation, followed by measuring the PPARγ1 transcriptional activity and translocation of FOXO1.Results: Our results show that like HF/HG, PPARγ1-K77 SUMOylation imitates endothelial IR and dysfunction, presenting decreased NO levels and elevated ET-1 levels, with PI3K/Akt/eNOS pathway inhibited, and endothelium-dependent vasodilation function impaired. Moreover, combination of HF/HG and PPARγ1-K77 SUMOylation exhibits a synergistic worsening effect on endothelial IR. Mechanistically, the results reveal that PPARγ1-K77 SUMOylation readily interacts with FOXO1, and the PPRE binding site of PI3K is competitively blocked by FOXO1, which represses PPARγ1 transcriptional activity and downregulates the PI3K-Akt pathway. Inhibition of the PI3K-Akt pathway promotes the nuclear accumulation of FOXO1, which interacts with SUMOylated PPARγ1 in the nucleus, exerting a positive feedback effect on IR pathogenesis.Conclusion: These results reveal a novel association between PPARγ1-K77 SUMOylation and FOXO1, which inhibits PPARγ1 transcriptional activity and contributes to vascular endothelial IR. These findings will be beneficial for better understanding the pathogenesis of endothelial IR and providing novel pharmacological targets for diabetic angiopathy.

In the Mood for Democracy? Democratic Support as Thermostatic Opinion

Public support has long been thought crucial for the vitality and survival of democracy. Existing research has argued that democracy also creates its own demand: through early-years socialization and later-life learning, the presence of a democratic system coupled with the passage of time produces widespread public support for democracy. Using new panel measures of democratic mood varying over 135 countries and up to 30 years, this article finds little evidence for such a positive feedback effect of democracy on support. Instead, it demonstrates a negative thermostatic effect: increases in democracy depress democratic mood, while decreases cheer it. Moreover, it is increases in the liberal, counter-majoritarian aspects of democracy, not the majoritarian, electoral aspects that provoke this backlash from citizens. These novel results challenge existing research on support for democracy, but also reconcile this research with the literature on macro-opinion.

Abstract 187: Constitutively Active Notch4 Elicits Brain Arteriovenous Malformations through Capillary Enlargement

Brain arteriovenous (AV) malformation (BAVM) is characterized by focal lesions of enlarged, tangled vessels that shunt blood from arteries to veins. BAVMs can rupture and cause life-threatening stroke. The origin of BAVM is currently unknown. We have developed a transgenic mouse model of BAVM via endothelial expression of constitutively-active Notch4 (Notch4*). Here, using two-photon excited fluorescence microscopy through chronically-implanted cranial windows, we obtained 4D data on the formation of BAVMs in live animals. We found that BAVMs arose from enlargement of pre-existing capillaries - judged as vessels with capillary diameter and blood flow as well as the absence of smooth muscle coverage. Capillary enlargement began promptly following the start of Notch4* expression and often occurred before increases in blood flow. Supporting the capillary origin of BAVMs, alterations in Notch signaling in endothelial cells of capillaries and veins, but not arteries, affected BAVM formation. Although the initiation of capillary enlargement was widespread, more proximal, lower resistance, AV connections grew into AVMs at the expense of more distal AV connections, by increasing in diameter and blood flow velocity through a positive feedback effect. Our data uncovers a mechanism underlying the focal BAVM formation elicited by a perturbation in gene expression throughout the endothelium.

Synergetic Concept of Algorithms Autonomous Inertial Navigation Systems

Errors of INS output parameters lead to a positive feedback effect of errors and eventually to an even more dramatic increase in system errors. To reduce the impact of this problem on the error output parameters of INS, in this paper, we propose and study a new concept of constructing algorithms for autonomous INS, which is called as synergetic concept. In the paper the synergetic concept of inertial system’s algorithm is presented and investigated by implementing its into strapdown inertial navigation system (SDINS).