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• W3175655166 abstract "Angiotensin converting enzyme 2 (ACE2) catalyzes the conversion of Angiotensin (Ang)-II to Ang-(1–7), attenuating the deleterious effects of angiotensin type 1 receptor (AT1R) activation on the cardiovascular functions. Our group originally demonstrated that increased Ang-II levels stimulate interactions between ACE2 and AT1R followed by enzyme degradation into lysosomes, overall leading to a diminished compensatory activity against overactive renin-angiotensin system. Although we showed that lysosomal inhibitors largely prevent Ang-II mediated hypertension in vivo, the cellular mechanisms regulating ACE2 degradation by elevated Ang-II remain largely unknown. To start elucidating these aspects, we performed a proteomic experiment in Neuro2A cells to find binding partners of ACE2 which interactions are modulated by Ang-II. Surprisingly, only fascin-1, an actin-bundling protein displayed differential interactions with ACE2 in these conditions, suggesting that it may be involved in ACE2 internalization and degradation. The interactions between ACE2 and fascin-1 were confirmed by confocal microscopy. These experiments also demonstrated that in control conditions ACE2/fascin-1 complexes are localized at the plasma membrane. Treatment with Ang-II (100 nM, 4 h) induced internalization of these complexes within cytoplasm. Preliminary experiments determining the total cellular levels of ACE2 in transfected HEK293T by western-blot demonstrated that Ang-II treatment for 18 h significantly decrease the cellular enzyme levels. In contrast, in cells overexpressing fascin-1, ACE2 cellular levels were preserved despite treatment with Ang-II. Similarly, in HEK293T cells co-transfected with ACE2 and AT1R, treatment with Ang-II (100 nM, 4 h) diminished the basal enzymatic activity (18382 ±2430) by 36 ±12%. Overexpression of fascin-1 did not significantly change ACE2 basal activity (86 ±24%), but in these cells Ang-II was unable to decrease enzymatic activity (85 ± 28% ). In conclusion, our results reveal for the first time a potential role of fascin-1 in cardiovascular diseases. As an ACE2 binding partner, fascin-1 may prevent enzyme degradation in presence of elevated Ang-II and it appears that its cellular levels are critical in prevention of the deleterious effects of overactive renin-angiotensin system. Also, these data highlight fascin-1 as an additional possible therapeutic target in the treatment of cardiovascular diseases. Support or Funding Information 5 P30 GM106392-03 (JJG). NHLBI HL093178 (EL) and a Bridge Grant from Howard University (CMF). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal." @default.
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• W3175655166 date "2018-04-01" @default.
• W3175655166 modified "2023-09-27" @default.
• W3175655166 title "Interactions of Angiotensin Converting Enzyme 2 with Fascin‐1 as a Novel Mechanism in Regulation of its Enzymatic Activity" @default.
• W3175655166 doi "https://doi.org/10.1096/fasebj.2018.32.1_supplement.lb324" @default.
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