Description: Background— Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss–independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1–dependent mechanism. Methods and Results— Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin 9-39 (10 μg·kg –1 ·h –1 ). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB. Conclusions— RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1–mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity.

Description: Objective— Coagulation factor XI (FXI) has been shown to contribute to thrombus formation on collagen or tissue factor–coated surfaces in vitro and in vivo by enhancing thrombin generation. Whether the role of the intrinsic pathway of coagulation is restricted to the local site of thrombus formation is unknown. This study was aimed to determine whether FXI could promote both proximal and distal platelet activation and aggregate formation in the bloodstream. Approach and Results— Pharmacological blockade of FXI activation or thrombin activity in blood did not affect local platelet adhesion, yet reduced local platelet aggregation, thrombin localization, and fibrin formation on immobilized collagen and tissue factor under shear flow, ex vivo. Downstream of the thrombus formed on immobilized collagen or collagen and 10 pmol/L tissue factor, platelet CD62P expression, microaggregate formation, and progressive platelet consumption were significantly reduced in the presence of FXI function-blocking antibodies or a thrombin inhibitor in a shear rate– and time-dependent manner. In a non-human primate model of thrombus formation, we found that inhibition of FXI reduced single platelet consumption in the bloodstream distal to a site of thrombus formation. Conclusions— This study demonstrates that the FXI–thrombin axis contributes to distal platelet activation and procoagulant microaggregate formation in the blood flow downstream of the site of thrombus formation. Our data highlight FXI as a novel therapeutic target for inhibiting distal platelet consumption without affecting proximal platelet adhesion.

Description: tFatty acids of microalgae have been studied as potential chemotaxonomic markers, to reveal plausi-ble lipid phycotoxins or in the context of mass production of algal biofuels. The planctonic microalgaeAlexandrium tamarense (Dinophyceae) is a common harmful algal bloom species that often proliferatesin eutrophic costal waters. Alexandrium blooms are the proximal source of toxins associated with par-alytic shellfish poisoning (PSP), a neurological affliction that has caused human illness for centuries viaconsumption of contaminated shellfish. However, data on the fatty acid composition of A. tamarense iscurrently limited. For this reason, we cultivated a well-defined strain of A. tamarense (Alex2, group I, NorthAmerican clade) in order to study both its major and minor fatty acids. The harvested microalgae weretransesterified and the fatty acid methyl esters were fractionated by means of high-speed counter-currentchromatography (HSCCC). The resulting 31 HSCCC fractions were analyzed by gas chromatography withmass spectrometry (GC/MS). Unknown substances were identified by transferring assorted HSCCC frac-tions into picolinyl or pyrrolidide derivatives. Twenty fatty acids (range 0.2–22.9% contribution to totalfatty acids) were identified in the unfractionated sample with 14:0, 16:0, 18:1n-9, 18:4n-3, 18:5n-3 and22:6n-3 representing 〉 80% of the total fatty acids. HSCCC fractionation enabled the identification of fur-ther 22 trace fatty acids contributing between ∼0.01 and 0.2% to total fatty acids. The fatty acids includedseveral branched-chain fatty acids as well as scarcely reported fatty acids like 11-methyl-18:1n-6tr or18:2�4,9. In order to enable a better comparability and repeatability of HSCCC fractionations, we calcu-lated for each HSCCC fraction the total volume of mobile phase, which had passed the HSCCC. From thisvolume we subtracted the volume of extruded stationary phase and divided the corrected volume by thetotal coil volume. These elution values were in good agreement with the partition ratios of randomlychosen fatty acid methyl esters obtained in shake flask tests, which allows the prediction of the elutionfrom the HSCCC system when the partition ratio is known.