Myocardial Infarction Research Laboratory - Cortese-Krott
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Chemistry and pharmacology of the chemical interaction of nitric oxide with sulfide in red blood cells.

By studying the chemical interaction of nitric oxide and sulfide under physiological conditions we discovered that chemical reactions occur between nitric oxide and sulfide leading to the formation of polysulfide and S-N hybrid species including SSNO- ( a NO and persulfide donor) and sulfiNO (nitroxyl and NO donor). These species induce vasodilation and modulate cardiac contractility both ex vivo and in vivo. Interestingly we found that red blood cells may play a central role in systemic sulfide metabolism: red blood cells produce sulfide and polysulfide and release these products in the supernatant in a reaction catalyzed by methemoglobin. Thereby, sulfide reduces methemoglobin back to deoxy/oxyhemoglobin, indicating the sulfide metabolic pathway in red blood cells may contribute to keeping hemoglobin in its reduced oxygen-binding form. 

  1. Bianco CL, Savitsky A, Feelisch M, Cortese-Krott MM. Investigations on the role of hemoglobin in sulfide metabolism by intact human red blood cells. Biochem Pharmacol. 2018 Mar;149:163-173. doi: 10.1016/j.bcp.2018.01.045. Epub 2018 Jan 31. PubMed PMID: 29409925.IF 4.235 5-Years-IF 4.752

  2. Cortese-Krott MM, Pullmann D, Feelisch M. Nitrosopersulfide (SSNO(-)) targets the Keap-1/Nrf2 redox system. Pharmacol Res. 2016 Sep 20;113(Pt A):490-499. doi: 10.1016/j.phrs.2016.09.022. [Epub ahead of print] PubMed PMID: 27663261. IF 4.816; 5-Years-IF 4391

  3. Cortese-Krott MM, Kuhnle GG, Dyson A, Fernandez BO, Grman M, DuMond JF, Barrow MP, McLeod G, Nakagawa H, Ondrias K, Nagy P, King SB, Saavedra JE, Keefer LK, Singer M, Kelm M, Butler AR, Feelisch M. Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl. Proc Natl Acad Sci USA. 2015 Aug 25;112:E4651-60. doi: 10.1073/pnas.1509277112. Epub 2015 Jul 29. IF 9.674; 5-Years-IF 10.563

  4. Cortese-Krott MM, Fernandez BO, Santos JL, Mergia E, Grman M, Nagy P, Kelm M, Butler A, Feelisch M. Nitrosopersulfide (SSNO(-)) accounts for sustained NO bioactivity of S-nitrosothiols following reaction with sulfide. Redox Biol. 2014 Jan 11;2:234-44. doi: 10.1016/j.redox.2013.12.031. IF 6.235; 5-Years-IF 7.613

  5. Cortese-Krott MM, Butler AR, Woollins JD, Feelisch M. Inorganic sulfur-nitrogen compounds: from gunpowder chemistry to the forefront of biological signaling. Dalton Trans. 2016 Apr 14;45(14):5908-19. doi:10.1039/c5dt05034k. PubMed PMID: 26898846. IF 4.029; 5-Years-IF 3.852

The role of a nitric oxide synthase in red blood cells for circulating nitrite homeostasis and systemic hemodynamics

 According to experiments carried out by using bone marrow transplantation chimera mice, there is strong evidence that eNOS in the blood may contribute to systemic circulating nitrite levels, blood pressure regulation, and cardioprotection.

  1. Leo F, Suvorava T, Heuser SK, Li J, LoBue A, Barbarino F, Piragine E, Schneckmann R, Hutzler B, Good ME, Fernandez BO, Vornholz L, Rogers S, Doctor A, Grandoch M, Stegbauer J, Weitzberg E, Feelisch M, Lundberg JO, Isakson BE, Kelm M, Cortese-Krott MM. Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure. Circulation. 2021 Sep 14;144(11):870-889. doi: 10.1161/CIRCULATIONAHA.120.049606. Epub 2021 Jul 7. PMID: 34229449; PMCID: PMC8529898.

  2. Wood KC*, Cortese-Krott MM,* Kovacic JC, Noguchi A, Liu VB, Wang X, Raghavachari N, Boehm M, Kato GJ, Kelm M, Gladwin MT. Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis. Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1861-1871. Epub 2013 May 23. IF 5.533; 5-Years-IF 6.430.

  3. Cortese-Krott MM, Kelm M. Endothelial nitric oxide synthase in red blood cells: Key to a new erythrocrine function? Redox Biol. 2014 Jan 9;2:251-258. Review. IF 6.235; IF 5-Years 7.613

  4. Cortese-Krott MM, Rodriguez-Mateos A, Sansone R, Kuhnle GG, Thasian-Sivarajah S, Krenz T, Horn P, Krisp C, Wolters D, Heiß C, Kröncke KD, Hogg N, Feelisch M, Kelm M. Human red blood cells at work: identification and visualization of erythrocytic eNOS activity in health and disease. Blood. 2012 Nov15;120(20):4229-37. doi: 10.1182/blood-2012-07-442277. Epub 2012 Sep 24. IF 9.060; 5-Years-IF 9.338

L-Arginine / nitric oxide signaling in the regulation of red cell function and dysfunction.

We found that red blood cells carry full Arginase1 (Arg1)/eNOS/soluble guanylate cyclase (sGC) signaling pathway and downstream signaling. Surprisingly, we found that eNOS produces NO in red blood cells under normoxic conditions. The pathophysiological role of L-Arginine/NO signaling in red blood cells for red blood cell function and dysfunction is still not clear yet. We found that nitric oxide signaling does not regulate red cell deformability per se, rather protects red blood cells from oxidant damage. Moreover, we studied whether L-Arg/NO signaling in red blood cells may regulate ATP release from red blood cells and found it to be independent of both cGMP and cAMP. We are currently analyzing the effects of red blood cell-specific genetic deletion of Arg1, eNOS, and sGC in vivo in mice obtained by the loxP/Cre technology on L-Arginine metabolism and red cell functional properties, including mechanical properties, the release of NO bioactivity, and vasodilation, cardioprotective activity ex vivo.

  1. Diederich L, Suvorava T, Sansone R, Keller TCS 4th, Barbarino F, Sutton TR, Kramer CM, Lückstädt W, Isakson BE, Gohlke H, Feelisch M, Kelm M, Cortese-Krott MM. On the effects of reactive oxygen species and nitric oxide on red blood cell deformability. Front Physiol. 2018 May 11;9:332. doi: 10.3389/fphys.2018.00332. eCollection 2018. PubMed PMID: 29867516; PubMed Central PMCID: PMC5958211.IF 4.134; 5-Years-IF 4.180

  2. Kuhn V, Diederich L, Keller TCS 4th, Kramer CM, Lückstädt W, Panknin C, Suvorava T, Isakson BE, Kelm M, Cortese-Krott MM. Red Blood Cell Function and dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia. Antioxid RedoxSignal. 2017 May 1;26(13):718-742. doi: 10.1089/ars.2016.6954. Epub 2017 Jan 18. Review. PubMed PMID: 27889956; PubMed Central PMCID: PMC5421513.IF 6.530; 5-Years-IF 7.389

  3. Cortese-Krott MM, Mergia E, Kramer CM, Lückstädt W, Yang J, Wolff G, Panknin C, Bracht T, Sitek B, Pernow J, Stasch JP, Feelisch M, Koesling D, Kelm M. Identification of a soluble guanylate cyclase in RBCs: preserved activity in patients with coronary artery disease. Redox Biol. 2018 Apr;14:328-337. doi: 10.1016/j.redox.2017.08.020. Epub 2017 Sep 8. PubMed PMID: 29024896; PubMed Central PMCID: PMC5975213. IF 7.126 5-Years-IF 7.613

  4. Keller AS, Diederich L, Panknin C, DeLalio LJ, Drake JC, Sherman R, JacksonEK, Yan Z, Kelm M, Cortese-Krott MM, Isakson BE. Possible roles for ATP release from RBCs exclude the cAMP-mediated Panx1 pathway. Am J Physiol Cell Physiol. 2017 Dec 1;313(6):C593-C603. doi: 10.1152/ajpcell.00178.2017. Epub 2017 Aug 30. PubMed PMID: 28855161; PubMed Central PMCID: PMC5814586.IF 3.454 5-Years-IF 3.547

Nitric oxide as a central player for cellular and systemic redox physiology

Nitric oxide plays a complex role in redox physiology acting as a signaling molecule, inducing post-translational modifications on cysteines, and participating in the regulation of the redox state. In my laboratory, we found that NO produced by the endothelial nitric oxide synthase is upregulated in a model of systemic oxidative stress induced by lack of the transcription factor Nrf2, and thereby fully preserves endothelial function and protect the heart from ischemic damage after acute myocardial infarction.

  1. Erkens R, Suvorava T, Sutton TR, Fernandez BO, Mikus-Lelinska M, Barbarino F, Flögel U, Kelm M, Feelisch M, Cortese-Krott MM. Nrf2 deficiency unmasks the significance of nitric oxide synthase activity for cardioprotection. Oxid Med Cell Longev. 2018 Apr 30;2018:8309698. doi: 10.1155/2018/8309698. eCollection 2018. PubMed PMID: 29854098; PubMed Central PMCID: PMC5952436. IF 4.936; 5-Years-IF 5.317

  2. Erkens R, Kramer CM, Lückstädt W, Panknin C, Krause L, Weidenbach M, Dirzka J, Krenz T, Mergia E, Suvorava T, Kelm M, Cortese-Krott MM. Left ventricular diastolic dysfunction in Nrf2 knock-out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function. Free Radic Biol Med. 2015 Dec;89:906-17. doi:10.1016 / j.freeradbiomed. 2015.10.409. PubMed PMID: 26475037.IF 5.736; 5-Years-IF 5.969

  3. Sutton TR, Minnion M, Barbarino F, Koster G, Fernandez BO, Cumpstey AF, Wischmann P, Madhani M, Frenneaux MP, Postle AD, Cortese-Krott MM, Feelisch M. A robust and versatile mass spectrometry platform for a comprehensive assessment of the thiol redox metabolome.Redox Biol. 2018 Jun;16:359-380. doi: 10.1016/j.redox.2018.02.012. Epub 2018 Feb 19. PMID: 29627744 IF 7.126; 5-Years-IF 7.613.

  4. Cortese-Krott MM, Koning A, Kuhnle GGC, Nagy P, Bianco CL, Pasch A, Wink DA, Fukuto JM, Jackson AA, van Goor H, Olson KR, Feelisch M. The reactive species interactome: evolutionary emergence, biological significance, and opportunities for redox metabolomics and personalized medicine. Antioxid Redox Signal. 2017 Oct 1;27(10):684-712. doi: 10.1089/ars.2017.7083. Epub 2017 Jun 6. Review. PubMed PMID: 28398072; PubMed Central PMCID: PMC5576088. IF 6.530; 5-Years-IF 7.389

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