000131659 001__ 131659 000131659 005__ 20240219150720.0 000131659 0247_ $$2doi$$a10.1164/rccm.201510-2058OC 000131659 0248_ $$2sideral$$a96826 000131659 037__ $$aART-2016-96826 000131659 041__ $$aeng 000131659 100__ $$aSchaer, Christian A. 000131659 245__ $$aHaptoglobin preserves vascular nitric oxide signaling during hemolysis 000131659 260__ $$c2016 000131659 5203_ $$aRationale: Hemolysis occurs not only in conditions such as sickle cell disease and malaria but also during transfusion of stored blood, extracorporeal circulation, and sepsis. Cell-free Hb depletes nitric oxide (NO) in the vasculature, causing vasoconstriction and eventually cardiovascular complications. We hypothesize that Hb-binding proteins may preserve vascular NO signaling during hemolysis. Objectives: Characterization of an archetypical function by which Hb scavenger proteins could preserve NO signaling during hemolysis. Methods: We investigated NO reaction kinetics, effects on arterial NO signaling, and tissue distribution of cell-free Hb and its scavenger protein complexes. Measurements and Main Results: Extravascular translocation of cell-free Hb into interstitial spaces, including the vascular smooth muscle cell layer of rat and pig coronary arteries, promotes vascular NO resistance. This critical disease process is blocked by haptoglobin. Haptoglobin does not change NO dioxygenation rates of Hb; rather, the large size of the Hb:haptoglobin complex prevents Hb extravasation, which uncouples NO/Hb interaction and vasoconstriction. Size-selective compartmentalization of Hb functions as a substitute for red blood cells after hemolysis and preserves NO signaling in the vasculature. We found that evolutionarily and structurally unrelated Hb-binding proteins, such as PIT54 found in avian species, functionally converged with haptoglobin to protect NO signaling by sequestering cell-free Hb in large protein complexes. Conclusions: Sequential compartmentalization of Hb by erythrocytes and scavenger protein complexes is an archetypical mechanism, which may have supported coevolution of hemolysis and normal vascular function. Therapeutic supplementation of Hb scavengers may restore vascular NO signaling and attenuate disease complications in patients with hemolysis. 000131659 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/ 000131659 590__ $$a13.204$$b2016 000131659 591__ $$aCRITICAL CARE MEDICINE$$b2 / 33 = 0.061$$c2016$$dQ1$$eT1 000131659 591__ $$aRESPIRATORY SYSTEM$$b2 / 59 = 0.034$$c2016$$dQ1$$eT1 000131659 592__ $$a6.136$$b2016 000131659 593__ $$aPulmonary and Respiratory Medicine$$c2016$$dQ1 000131659 593__ $$aCritical Care and Intensive Care Medicine$$c2016$$dQ1 000131659 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000131659 700__ $$aDeuel, Jeremy W. 000131659 700__ $$aSchildknecht, Daniela 000131659 700__ $$aMahmoudi, Leila 000131659 700__ $$0(orcid)0000-0002-1827-1250$$aGarcia-Rubio, Ines 000131659 700__ $$aOwczarek, Catherine 000131659 700__ $$aSchauer, Stefan 000131659 700__ $$aKissner, Reinhard 000131659 700__ $$aBanerjee, Uddyalok 000131659 700__ $$aPalmer, Andre F. 000131659 700__ $$aSpahn, Donat R. 000131659 700__ $$aIrwin, David C. 000131659 700__ $$aVallelian, Florence 000131659 700__ $$aBuehler, Paul W. 000131659 700__ $$aSchaer, Dominik J. 000131659 773__ $$g193, 10 (2016), 1111-1122$$pAm. j. respir. crit. care med.$$tAmerican Journal of Respiratory and Critical Care Medicine$$x1073-449X 000131659 8564_ $$s3548037$$uhttps://zaguan.unizar.es/record/131659/files/texto_completo.pdf$$yVersión publicada 000131659 8564_ $$s2668432$$uhttps://zaguan.unizar.es/record/131659/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000131659 909CO $$ooai:zaguan.unizar.es:131659$$particulos$$pdriver 000131659 951__ $$a2024-02-19-13:22:30 000131659 980__ $$aARTICLE