Hemoglobin α/eNOS coupling at myoendothelial junctions is required for nitric oxide scavenging during vasoconstriction.

نویسندگان

  • Adam C Straub
  • Joshua T Butcher
  • Marie Billaud
  • Stephanie M Mutchler
  • Mykhaylo V Artamonov
  • Anh T Nguyen
  • Tyler Johnson
  • Angela K Best
  • Megan P Miller
  • Lisa A Palmer
  • Linda Columbus
  • Avril V Somlyo
  • Thu H Le
  • Brant E Isakson
چکیده

OBJECTIVE Hemoglobin α (Hb α) and endothelial nitric oxide synthase (eNOS) form a macromolecular complex at myoendothelial junctions; the functional role of this interaction remains undefined. To test if coupling of eNOS and Hb α regulates nitric oxide signaling, vascular reactivity, and blood pressure using a mimetic peptide of Hb α to disrupt this interaction. APPROACH AND RESULTS In silico modeling of Hb α and eNOS identified a conserved sequence of interaction. By mutating portions of Hb α, we identified a specific sequence that binds eNOS. A mimetic peptide of the Hb α sequence (Hb α X) was generated to disrupt this complex. Using in vitro binding assays with purified Hb α and eNOS and ex vivo proximity ligation assays on resistance arteries, we have demonstrated that Hb α X significantly decreased interaction between eNOS and Hb α. Fluorescein isothiocyanate labeling of Hb α X revealed localization to holes in the internal elastic lamina (ie, myoendothelial junctions). To test the functional effects of Hb α X, we measured cyclic guanosine monophosphate and vascular reactivity. Our results reveal augmented cyclic guanosine monophosphate production and altered vasoconstriction with Hb α X. To test the in vivo effects of these peptides on blood pressure, normotensive and hypertensive mice were injected with Hb α X, which caused a significant decrease in blood pressure; injection of Hb α X into eNOS(-/-) mice had no effect. CONCLUSIONS These results identify a novel sequence on Hb α that is important for Hb α/eNOS complex formation and is critical for nitric oxide signaling at myoendothelial junctions.

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عنوان ژورنال:
  • Arteriosclerosis, thrombosis, and vascular biology

دوره 34 12  شماره 

صفحات  -

تاریخ انتشار 2014