Administration of the KCa channel activator SKA-31 improves endothelial function in the aorta of atherosclerosis-prone mice.

INTRODUCTION: Atherosclerosis remains a major risk factor for vascular dysfunction and cardiovascular (CV) disease. Pharmacological enhancement of endothelial Ca2+-activated K+ channel activity (i.e., KCa2.3 and KCa3.1) opposes vascular dysfunction associated with ageing and type 2 diabetes (T2D) in ex vivo and in vivo preparations. In the current study, we have investigated the efficacy of this strategy to mitigate endothelial dysfunction in the setting of atherogenesis. METHODS: Male apolipoprotein E knockout (Apoe-/-) mice fed a high fat diet (HFD) were treated daily with the KCa channel activator SKA-31 (10 mg/kg), the KCa3.1 channel blocker senicapoc (40 mg/kg), or drug vehicle for 12-weeks. Endothelium-dependent and -independent relaxation and vasocontractility were measured in abdominal aorta by wire myography. The development of atherosclerosis in the thoracic aorta was characterized by Oil Red O staining and immunohistochemistry. Key vasorelaxant signaling proteins were quantified by q-PCR. RESULTS: Endothelium-dependent relaxation of phenylephrine-constricted aortic rings was impaired in Apoe-/- HFD mice (53%) vs. wild-type (WT) controls (80%, P < 0.0001), consistent with endothelial dysfunction. Treatment of Apoe-/- HFD mice with SKA-31, but not senicapoc, restored maximal relaxation to the WT level. Phenylephrine-evoked contraction was similar in WT and vehicle/drug treated Apoe-/- mice, as was the maximal relaxation induced by the endothelium-independent vasodilator sodium nitroprusside. mRNA expression for eNOS, KCa3.1, KCa2.3 and TRPV4 channels in the abdominal aorta was unaffected by either SKA-31 or senicapoc treatment. Fatty plaque formation, tissue collagen, α-smooth muscle actin and resident macrophages in the aortic sinus were also unaltered by either treatment vs. vehicle treated Apoe-/- HFD mice. CONCLUSION: Our data show that prolonged administration of the KCa channel activator SKA-31 improved endothelial function without modifying fatty plaque formation in the aorta of Apoe-/- mice

The institutions of archaic post-modernity and their organizational and managerial consequences: The case of Portugal

The long march of modernization of the Western societies tends to be presented as following a regular sequence: societies and institutions were pre-modern, and then they were modernized, eventually becoming post-modern. Such teleology may provide an incomplete or distorted narrative of societal evolution in many parts of the world, even in the ‘post-modern heartland’ of Western Europe, with Portugal being a case in point. The concept of archaic post-modernity has been developed by a philosopher, José Gil, to show how Portuguese institutions and organizations combine elements of pre-modernity and post-modernity. The notion of an archaic post-modernity is advanced in order to provide an alternative account of the modernization process, which enriches discussion of the varieties of capitalism. Differences in historical experiences create singularities that may be considered in the analysis of culture, management and organization

Role of <i>O</i>-GlcNAcylation in nutritional sensing, insulin resistance and in mediating the benefits of exercise

The purpose of this review is to highlight the role of O-linked β-N-acetylglucosamine (O-GlcNAc) protein modification in metabolic disease states and to summarize current knowledge of how exercise affects this important post-translational signalling pathway. O-GlcNAc modification is an intracellular tool capable of integrating energy supply with demand. The accumulation of excess energy associated with obesity and insulin resistance is mediated, in part, by the hexosamine biosynthetic pathway (HBP), which results in the O-GlcNAcylation of a myriad of proteins, thereby affecting their respective function, stability, and localization. Insulin resistance is related to the excessive O-GlcNAcylation of key metabolic proteins causing a chronic blunting of insulin signalling pathways and precipitating the accompanying pathologies, such as heart and kidney disease. Lifestyle modifications such as diet and exercise also modify the pathway. Exercise is a front-line and cost-effective therapeutic approach for insulin resistance, and recent work shows that the intervention can alter O-GlcNAc gene expression, signalling, and protein modification. However, there is currently no consensus on the effect of frequency, intensity, type, and duration of exercise on O-GlcNAc modification, the HBP, and its related enzymes. On one end of the spectrum, mild, prolonged swim training reduces O-GlcNAcylation, while on the other end, higher intensity treadmill running increases cardiac protein O-GlcNAc modification. Clearly, a balance between acute and chronic stress of exercise is needed to reap the benefits of the intervention on O-GlcNAc signalling. </jats:p

Effects of hypothermia on energy metabolism in rat and Richardson’s ground squirrel hearts

Belke, Darrell D., Lawrence C. H. Wang, and Gary D. Lopaschuk. Effects of hypothermia on energy metabolism in rat and Richardson’s ground squirrel hearts. J. Appl. Physiol. 82(4): 1210–1218, 1997.—Glycolysis, glucose oxidation, palmitate oxidation, and cardiac function were measured in isolated working hearts from ground squirrels and rats subjected to a hypothermia-rewarming protocol. Hearts were perfused initially for 30 min at 37°C, followed by 2 h of hypothermic perfusion at 15°C, after which hearts were rewarmed to 37°C and further perfused for 30 min. Functional recovery in ground squirrel hearts was greater than in rat hearts after rewarming. Hypothermia-rewarming had a similar general effect on the various metabolic pathways in both species. Despite these similarities, total energy substrate metabolic rates were greater in rat than ground squirrel hearts during hypothermia despite a lower level of work being performed by the rat hearts, indicating that rat hearts are less efficient than ground squirrel hearts during hypothermia. After rewarming, energy substrate metabolism recovered completely in both species, although cardiac work remained depressed in rat hearts. The difference in functional recovery between rat and ground squirrel hearts after rewarming cannot be explained by general differences in energy substrate metabolism during hypothermia or after rewarming.</jats:p