Current research supports that obesity and insulin resistance are positively correlated with plasma endothelin‐1 (ET‐1) levels; however, the mechanisms leading to this increase in ET‐1 are not fully understood. Similarly, while some physiological effects of ET‐1 have been characterized, the full complexity of this hormone has yet to be described in tissues outside of the vascular system. To date, one of the best treatments available for morbid obesity, cardiovascular disease, and metabolic syndrome is bariatric surgery to quickly reduce body fat and the factors associated with obesity‐related disease. We hypothesize that vertical sleeve gastrectomy (VSG) will reduce plasma ET‐1 levels. This was tested by measuring plasma ET‐1 levels from twelve obese patients before VSG, 6 weeks after, and 6 months after surgery. The results indicate that 6 weeks following VSG, plasma ET‐1 levels increased by 24%; however, after 6 months, there was a 27% decrease compared to baseline. Average weight loss in this cohort was 11.3±2.4 percent body weight after 6 weeks and 21.4±5.7 percent body weight after 6 months. Interestingly, we observed an inverse relationship between baseline plasma ET‐1 and percent body weight loss 3 months (R2=0.45, p<0.05) and 6 months (R2=0.49, p=0.01) post bariatric surgery. Our results indicate that VSG reduces plasma ET‐1 levels, a possible mechanism for improved metabolic risk in these patients. These data also suggest that ET‐1 may inhibit weight loss or serve as a predictor of weight loss following bariatric surgery. Support or Funding Information This work is supported by NHLBI grant R00 HL127178 to JSS. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Current research supports that obesity and insulin resistance are positively correlated with plasma endothelin‐1 (ET‐1) levels; however, the mechanisms leading to this increase in ET‐1 are not fully understood. Similarly, while some physiological effects of ET‐1 have been characterized, the full complexity of this hormone has yet to be described in tissues outside of the vascular system. To date, one of the best treatments available for morbid obesity, cardiovascular disease, and metabolic syndrome is bariatric surgery to quickly reduce body fat and the factors associated with obesity‐related disease. We hypothesize that vertical sleeve gastrectomy (VSG) will reduce plasma ET‐1 levels. This was tested by measuring plasma ET‐1 levels from twelve obese patients before VSG, 6 weeks after, and 6 months after surgery. The results indicate that 6 weeks following VSG, plasma ET‐1 levels increased by 24%; however, after 6 months, there was a 27% decrease compared to baseline. Average weight loss in this cohort was 11.3±2.4 percent body weight after 6 weeks and 21.4±5.7 percent body weight after 6 months. Interestingly, we observed an inverse relationship between baseline plasma ET‐1 and percent body weight loss 3 months (R2=0.45, p<0.05) and 6 months (R2=0.49, p=0.01) post bariatric surgery. Our results indicate that VSG reduces plasma ET‐1 levels, a possible mechanism for improved metabolic risk in these patients. These data also suggest that ET‐1 may inhibit weight loss or serve as a predictor of weight loss following bariatric surgery.Support or Funding InformationThis work is supported by NHLBI grant R00 HL127178 to JSS.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Preeclampsia (PE) is a hypertensive disorder of pregnancy which affects ~5–7% of all pregnancies in the United States. Hallmarked by new‐onset hypertension and organ damage, it is a leading cause of premature birth and maternal/fetal perinatal morbidity. While the cause of PE remains elusive, placental dysfunction due to chronic ischemia is believed to be a central regulator of the disorder. One of the factors known to be released from the ischemic placenta is the soluble form of the VEGF receptor Flt‐1 (sFlt‐1), which is released into the maternal circulation and is believed to be a major contributor to the maternal endothelial dysfunction seen in PE. It has been hypothesized that restoring angiogenic balance by way of administration of VEGF family members could be beneficial in PE. To that end, we have recently described several novel VEGF family‐based chimeric proteins with enhanced bioavailability and improved pharmacokinetic profiles. Recently, we have demonstrated that in vivo administration of a VEGFA‐based chimeric therapeutic protein was able to relieve the symptoms of PE in a rodent model, but resulted in adverse effects at dose‐limiting toxicity; in particular a marked increase in the circulating levels of sFlt‐1. Here we hypothesize that chimeric therapeutics based on the VEGF family members Placental Growth Factor (PlGF) and VEGFB will cause reduced production of sFlt‐1 from placental and vascular cells when compared to their VEGFA counterpart. To that end, we utilized cultured rodent placental explants, cultured BeWo cells derived from placental syncytiotrophoblasts, and primary Human Umbilical Vein Endothelial Cells (HUVEC) cells to determine the relative effects of the VEGF chimeras on sFlt‐1 production. Incubation of HUVECs with chimeric VEGFA caused a significant increase in released sFlt‐1 (6593±199 vs 14547±364 pg/ml, p<0.0001), while there was no induction with either chimeric PlGF (6830±88pg/ml) or VEGFB (7217±71pg/ml). To further elucidate the effects of chimeric VEGFA on HUVEC sFlt‐1 production, we examined three splice variants of sFlt‐1 as well as the full length Flt‐1 by qRT‐PCR. In response to VEGF, the β‐Actin normalized expression increased in sFlt v2 (100±34% vs 401±36%, p<0.0001), a trend to increase full length Flt‐1 message (100±34% vs 177±20%, p=−0.11) and sFlt‐1 v3 (123±8%, p=0.16) with no effect on sFlt v4 (100±34% vs 68±8%, p=0.36). This VEGF induced sFlt‐1 release was significantly attenuated with either a dual VEGFR1/VEGFR2 antagonist or a VEGR2 specific antagonist, but not a neuropilin‐1 selective antagonist, suggesting the receptor responsible for the release of sFlt‐1 in response to VEGF is the VEGFR2 receptor. In conclusion we conclude that the significant in vivo increase in sFlt‐1 caused by chronic chimeric VEGF administration is due to increased endothelial production of sFlt‐1. This is associated with increase production of the sFlt‐1 v2 splice variant, and is likely due to activation of the VEGFR2 receptor.Support or Funding InformationThis work was funded in part by NIH grants P01HL51971, P20GM104357, T32HL105324, R00HL11677, R25 HL121042‐01, and R01HL 137791.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Elevated endothelin‐1 (ET‐1) is associated with obesity, as well as insulin resistance. We previously reported that rats lacking functional endothelin type B receptors (ETB) demonstrate improved glucose control. In addition, ETB receptor deficient rats have hypertension due to overactivation of the endothelin type A receptor (ETA). In order to determine the effects of ETA receptor activation on insulin sensitivity, we tested the hypothesis that pharmacological blockade of ETB receptors and dual ETA/ETB receptor inhibition would improve glucose control in Sprague Dawley (SD) rats. SD rats were treated with Bosentan (30 mg/kg/day), Atrasentan (10 mg/kg/day), A‐192621 (10 mg/kg/day), or vehicle over a period of two weeks. At day 7, insulin tolerance testing was performed and tissues were collected at day 14 after a 6‐hour fasting period. Treatment with either the dual ETA/ETB antagonist Bosentan, or the ETB antagonist A‐192621, significantly lowered fasting blood glucose as compared to either vehicle or ETA antagonist (Atrasentan) (82.72±4.2*, 75±6.1*, 99.1±2.0, and 94.8±3.2 mg/dl respectively, *p<0.05 vs. vehicle). In addition, both Bosentan and A‐192621 improved insulin tolerance compared to vehicle treated, while Atrasentan had no effect. There were no differences in plasma cholesterol (LDL or HDL) or triglycerides. These data indicate that blockade of ETB receptors improves glucose control and may be an effective treatment for insulin resistance and pre‐diabetes.Support or Funding InformationThis work is supported by NHLBI grant R00 HL127178 to JSS.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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