Depletion of circulating blood NOS3 increases severity of myocardial infarction and left ventricular dysfunction
Open accessAbstract
Nitric oxide (NO) derived from endothelial NO synthase (NOS3) plays a central role in myocardial ischemia/reperfusion (I/R)-injury. Subsets of circulating blood cells, including red blood cells (RBCs), carry a NOS3 and contribute to blood pressure regulation and RBC nitrite/nitrate formation. We hypothesized that the circulating blood born NOS3 also modulates the severity of myocardial infarction in disease models. We cross-transplanted bone marrow in wild-type and NOS3(-/-) mice with wild-type mice, producing chimeras expressing NOS3 only in vascular endothelium (BC-/EC+) or in both blood cells and vascular endothelium (BC+/EC+). After 60-min closed-chest coronary occlusion followed by 24 h reperfusion, cardiac function, infarct size (IS), NOx levels, RBCs NO formation, RBC deformability, and vascular reactivity were assessed. At baseline, BC-/EC+ chimera had lower nitrite levels in blood plasma (BC-/EC+: 2.13 ± 0.27 μM vs. BC+/EC+ 3.17 ± 0.29 μM; *p < 0.05), reduced DAF FM associated fluorescence within RBCs (BC-/EC+: 538.4 ± 12.8 mean fluorescence intensity (MFI) vs. BC+/EC+: 619.6 ± 6.9 MFI; ***p < 0.001) and impaired erythrocyte deformability (BC-/EC+: 0.33 ± 0.01 elongation index (EI) vs. BC+/EC+: 0.36 ± 0.06 EI; *p < 0.05), while vascular reactivity remained unaffected. Area at risk did not differ, but infarct size was higher in BC-/EC+ (BC-/EC+: 26 ± 3 %; BC+/EC+: 14 ± 2 %; **p < 0.01), resulting in decreased ejection fraction (BC-/EC+ 46 ± 2 % vs. BC+/EC+: 52 ± 2 %; *p < 0.05) and increased end-systolic volume. Application of the NOS inhibitor S-ethylisothiourea hydrobromide was associated with larger infarct size in BC+/EC+, whereas infarct size in BC-/EC+ mice remained unaffected. Reduced infarct size, preserved cardiac function, NO levels in RBC and RBC deformability suggest a modulating role of circulating NOS3 in an acute model of myocardial I/R in chimeric mice.
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Chimera mice lacking eNOS in blood have increased infarct sizes after myocardial ischemia/reperfusion injury.
“as well as increased infarct sizes after myocardial ischemia/reperfusion injury (73, 125).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [125]
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Cites
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“levels of circulating nitrite likely contribute to the greater tissue damage in BC-/EC? chimeras, as previously shown in WT mice [13, 14].”
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Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia
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“…irradiated and bone marrow transplanted mice (chimeras) that were lacking eNOS in blood; these chimera mice present a hypertensive phenotype along with decreased circulating nitrite and nitrate levels (196), as well as increased infarct sizes after myocardial ischemia/reperfusion injury (73, 125).”
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“In an acute model of myocardial ischemia/reperfusion we found that chimeras lacking blood cell eNOS had increased infarct size, resulting in decreased ejection fraction and increased end systolic volume after 60 min ischemia and 24 h of reperfusion [82].”
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“Echocardiographic measurements were performed in anesthetized male mice from the 3 study groups (WT, R92Q, and E163R), using a standardized protocol.(31) Average heart rate during echocardiographic measurement was similar in the 3 groups: 585 42 beats per minute in WT, 579 38 beats per minute in E163R, and 573 45 beat…”
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Self-citationCortese-Krott, M. M., Mergia, E., Kramer, C. M., Lückstädt, W., Yang, J., Wolff, G., Panknin, C., Bracht, T., Sitek, B., Pernow, J., et al. (2017) · Redox Biology · doi:10.1016/j.redox.2017.08.020 · Cited by 70 · see citing works
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“specific to erythrocytes (and all bone marrow-derived cells), plasma NOx was reduced and greater severity of infarct pathologies were noted (Merx et al., 2014; Wood et al., 2013).”
BackgroundMüller, J., Gorreßen, S., Grandoch, M., Feldmann, K., Kretschmer, I., Lehr, S., Ding, Z., Schmitt, J. P., Schrader, J., Garbers, C., et al. (2014) · Basic Research in Cardiology · doi:10.1007/s00395-014-0440-y · Cited by 66 · see citing works
Self-citationYang, J., Zheng, X., Mahdi, A., Zhou, Z., Tratsiakovich, Y., Jiao, T., Kiss, A., Kövamees, O., Alvarsson, M., Catrina, S., et al. (2018) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2018.03.006 · Cited by 66 · see citing works
“Furthermore, mice with blood cells lacking eNOS have lower circulating nitrite and nitrate levels and develop larger infarcts following ischemia-reperfusion than control mice, supporting a role of RBC eNOS also under in vivo conditions (14,30).”
BackgroundNovel perspectives on redox signaling in red blood cells and platelets in cardiovascular disease
Mahdi, A., Cortese-Krott, M. M., Kelm, M., Li, N., & Pernow, J. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.03.020 · Cited by 63 · see citing works
Self-citationErythrocytes as markers of oxidative stress related pathologies
Massaccesi, L., Galliera, E., & Romanelli, M. M. C. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111333 · Cited by 60 · see citing works
Wischmann, P., Kuhn, V., Suvorava, T., Muessig, J. M., Fischer, J. W., Isakson, B. E., Haberkorn, S. M., Flögel, U., Schrader, J., Jung, C., et al. (2020) · Basic Research in Cardiology · doi:10.1007/s00395-020-0799-x · Cited by 56 · see citing works
Self-citationIdentification of ILK as a critical regulator of VEGFR3 signalling and lymphatic vascular growth
Urner, S., Planas‐Paz, L., Hilger, L. S., Henning, C., Branopolski, A., Kelly‐Goss, M. R., Stanczuk, L., Pitter, B., Montañez, E., Peirce, S. M., et al. (2018) · The EMBO Journal · doi:10.15252/embj.201899322 · Cited by 55 · see citing works
“Therefore, mice underwent a pre-surgery 1 week after the last tamoxifen injection, in which the suture was placed underneath the LAD, in principle following the detailed protocol described in Merx et al (2014).”
Erkens, R., Suvorava, T., Kramer, C. M., Diederich, L., Kelm, M., & Cortese-Krott, M. M. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6904 · Cited by 53 · see citing works
“To untangle the role of vascular and blood components responsible for eNOSmediated heterocellular signaling, we created chimera mice by bone marrow transplantation (103, 153).”
MethodSelf-citationNrf2 Deficiency Unmasks the Significance of Nitric Oxide Synthase Activity for Cardioprotection
Erkens, R., Suvorava, T., Sutton, T. R., Fernandez, B. O., Mikus-Lelinska, M., Barbarino, F., Flögel, U., Kelm, M., Feelisch, M., & Cortese-Krott, M. M. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/8309698 · Cited by 42 · see citing works
“In contrast, a study from our laboratory proposed a potential key role of the red blood cell eNOS in cardioprotection against I/R [50].”
Self-citationChen, C., Chen, W., Nong, Z., Ma, Y., Qiu, S., & Wu, G. (2016) · Cellular Physiology and Biochemistry · doi:10.1159/000445561 · Cited by 43 · see citing works
RetractedMitochondrial bioenergetics links inflammation and cardiac contractility in endotoxemia
Vico, T. A., Marchini, T., Ginart, S., Lorenzetti, M. A., Areán, J. S. A., Calabró, V., Garcés, M., Ferrero, M. C., Mazo, T., D’Annunzio, V., et al. (2019) · Basic Research in Cardiology · doi:10.1007/s00395-019-0745-y · Cited by 38 · see citing works
The role of globins in cardiovascular physiology
Keller, T. C. S., Lechauve, C., Keller, A., Brooks, S., Weiss, M. J., Columbus, L. M., Ackerman, H. C., Cortese-Krott, M. M., & Isakson, B. E. (2021) · Physiological Reviews · doi:10.1152/physrev.00037.2020 · Cited by 37 · see citing works
Self-citationZhuge, Z., Haworth, S. M., Nihlén, C., Carvalho, L. R. R. A., Heuser, S. K., Kleschyov, A. L., Nasiell, J., Cortese-Krott, M. M., Weitzberg, E., Lundberg, J. O., et al. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102612 · Cited by 32 · see citing works
Self-citationCirculating NOS3 Modulates Left Ventricular Remodeling following Reperfused Myocardial Infarction
Gorressen, S., Stern, M., van de Sandt, A. M., Cortese-Krott, M. M., Ohlig, J., Rassaf, T., Gödecke, A., Fischer, J. W., Heusch, G., Merx, M. W., et al. (2015) · PLOS ONE · doi:10.1371/journal.pone.0120961 · Cited by 29 · see citing works
“chimerae which either do (BC+/EC+) or do not carry NOS3 in blood cells (BC−/EC+) as described previously [8, 16].”
BackgroundMethodInfluentialSelf-citationRed blood cell eNOS is cardioprotective in acute myocardial infarction
Cortese-Krott, M. M., Suvorava, T., Leo, F., Heuser, S. K., LoBue, A., Li, J., Becher, S., Schneckmann, R., Srivrastava, T., Erkens, R., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102370 · Cited by 29 · see citing works
Self-citation., P., Sharma, M., Singh, K., Himashree, G., Bhaumik, G., Kumar, B., & Sethy, N. K. (2020) · Nitric Oxide · doi:10.1016/j.niox.2020.05.003 · Cited by 28 · see citing works
Niermann, C., Gorreßen, S., Klier, M., Gowert, N. S., Billuart, P., Kelm, M., Merx, M. W., & Elvers, M. (2016) · Cellular Signalling · doi:10.1016/j.cellsig.2016.04.008 · Cited by 27 · see citing works
Self-citationPagliaro, P., Weber, N. C., Femminò, S., Alloatti, G., & Penna, C. R. R. (2024) · Basic Research in Cardiology · doi:10.1007/s00395-024-01061-1 · Cited by 26 · see citing works
“Nitric oxide can also be generated in tissues through either direct disproportionation or the reduction of nitrate and nitrite to NO under acidic and highly reduced conditions that are present in disease states like ischemia [70, 94, 117, 119, 223].”
BackgroundRed blood cell endothelial nitric oxide synthase: A major player in regulating cardiovascular health
LoBue, A., Heuser, S. K., Lindemann, M., Li, J., Rahman, M., Kelm, M., Stegbauer, J., & Cortese-Krott, M. M. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16230 · Cited by 28 · see citing works
“…obtained by transplantation of eNOS KO bone marrow into WT mice showed an increased infarct size, LV dysfunction and worsened remodelling after AMI (Merx et al., 2014 The targeting procedure for EC using a Cdh5-Cre/ERT2 construct (i.e., a tamoxifen-inducible Cre-recombinase under control of the…”
InfluentialSelf-citationKaakinen, M., Reichelt, M. E., Ma, Z., Ferguson, C., Martel, N., Porrello, E. R., Hudson, J. E., Thomas, W. G., Parton, R. G., & Headrick, J. P. (2017) · Basic Research in Cardiology · doi:10.1007/s00395-017-0613-6 · Cited by 21 · see citing works
“Furthermore, local and peripheral vascular eNOS activities [5, 79, 101], together with circulating eNOS [40, 64], may influence myocardial function or phenotype.”
BackgroundCortese-Krott, M. M. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8171 · Cited by 20 · see citing works
“We and others have found that RBCs also carry an active endothelial nitric oxide synthase (eNOS) (25) and the NO receptor soluble guanylate cyclase (sGC) (24), and thereby they participate in blood pressure regulation and cardioprotection (91, 158).”
Self-citationPioner, J. M., Vitale, G., Gentile, F. R., Scellini, B., Piroddi, N., Cerbai, E., Olivotto, I., Tardiff, J. C., Coppini, R., Tesi, C., et al. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.864547 · Cited by 20 · see citing works
“Echocardiographic measurements were performed in anesthetized male mice from the three study groups (WT, R92Q, and E163R), using a standardized protocol (Merx et al., 2014) and focussing on the atrial characteristics and LV diastolic function.”
MethodExtracellular ATP activates eNOS and increases intracellular NO generation in Red Blood Cells
Ülker, P., Özen, N., Abdullayeva, G., Köksoy, S., Yaraş, N., & Basralı, F. (2017) · Clinical Hemorheology and Microcirculation · doi:10.3233/ch-170326 · Cited by 19 · see citing works
“Besides, important roles of RBC eNOS enzyme activity on the physiological regulation of blood flow, blood pressure, and myocardial function, have been demonstrated by previous studies [8–13].”
Kronenbitter, A. V., Funk, F., Hackert, K., Gorreßen, S., Glaser, D., Boknı́k, P., Poschmann, G., Stühler, K., Isić, M., Krüger, M., et al. (2018) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2018.04.004 · Cited by 18 · see citing works
Porro, B., Eligini, S., Squellerio, I., Tremoli, E., & Cavalca, V. (2014) · Biochemical Society Transactions · doi:10.1042/bst20140122 · Cited by 18 · see citing works
Jiao, T., Collado, A., Mahdi, A., Jurga, J., Tengbom, J., Saleh, N., Verouhis, D., Böhm, F., Zhou, Z., Yang, J., et al. (2022) · Basic Research in Cardiology · doi:10.1007/s00395-022-00953-4 · Cited by 16 · see citing works
Clasen, L., Angendohr, S., Becher, S., Bartsch, B., Enkel, S., Meyer, C. G., Kelm, M., Makimoto, H., & Klöcker, N. (2023) · Scientific Reports · doi:10.1038/s41598-023-32346-5 · Cited by 15 · see citing works
Self-citationWang, X., Yang, G., Li, J., Meng, C., & Xue, Z. (2024) · Scientific Reports · doi:10.1038/s41598-024-60945-3 · Cited by 14 · see citing works
“Previous studies have shown that circulating NOS3 modulates left ventricular remodeling following reperfused myocardial infarction 44,45 .”
BackgroundTotzeck, M., Hendgen-Cotta, U. B., French, B. A., & Rassaf, T. (2016) · Journal of Biological Methods · doi:10.14440/jbm.2016.149 · Cited by 12 · see citing works
“Taking together, the infarction model has been applied in a wide variety of studies and has proven excellent reproducibility [9,16,24,33,34].”
MethodSelf-citationRed cell distribution width in anemic patients undergoing transcatheter aortic valve implantation
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Hematopoietic Cell–Expressed Endothelial Nitric Oxide Protects the Liver From Insulin Resistance
Dick, B. P., McMahan, R. S., Knowles, T. O., Becker, L., Gharib, S. A., Vaisar, T., Wietecha, T., O’Brien, K. D., Bornfeldt, K., Chait, A., et al. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.313648 · Cited by 6 · see citing works
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Muessig, J. M., Kaya, S., Moellhoff, L., Noelle, J., Pareja, L. H., Masyuk, M., Gerdes, N., Pernow, J., Kelm, M., & Jung, C. (2019) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248419874348 · Cited by 6 · see citing works
“These time- and cost-intensive models are traditionally used to examine blood cell-specific signaling pathways on the one hand and vascular cell- and cardiomyocyte-related responses on the other hand in the setting of myocardial I/R injury.(23,24) The use of blood from genetically modified mouse models to an isolated…”
MethodSelf-citationConditioning medicine for ischemic and hemorrhagic stroke.
Hess, D. C., Khan, M. B., Kamat, P. K., Vaibhav, K., Dhandapani, K. M., Baban, B., Waller, J. L., Hoda, N., Blauenfeldt, R. A., & Andersen, G. (2021) · PubMed · Cited by 6 · see citing works
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Кутихин, А. Г. (2021) · Fundamental and Clinical Medicine · doi:10.23946/2500-0764-2021-6-1-82-102 · Cited by 5 · see citing works
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Self-citationRho-kinase is a negative regulator of red blood cell eNOS under basal conditions
Ülker, P., Özen, N., Abduleyeva, G., Köksoy, S., Yaraş, N., & Basralı, F. (2019) · Clinical Hemorheology and Microcirculation · doi:10.3233/ch-190578 · Cited by 5 · see citing works
“Considering increased ROCK activity contributes to progression of several cardiovascular diseases and RBC are important regulators of blood pressure and blood flow regulation [8–13, 20, 22, 23], the pathway described herein might also be more important under pathological conditions.”
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“…acute model of myocardial ischemia/reperfusion (I/R) in chimeric mice, erythrocyte eNOS was found to be essential in reducing the infarct size, preserving cardiac function, and maintaining optimal nitric oxide levels in RBCs [25]. function, and maintaining optimal nitric oxide levels in RBCs [25].”
BackgroundObscurin deficiency leads to compensated dilated cardiomyopathy and increased arrhythmias
Pioner, J. M., Pierantozzi, E., Coppini, R., Rubino, E. M., Biasci, V., Vitale, G., Laurino, A., Santini, L., Scardigli, M., Randazzo, D., et al. (2025) · The Journal of General Physiology · doi:10.1085/jgp.202413696 · Cited by 2 · see citing works
“Compensated DCM phenotype in Obscn KO hearts Echocardiographic measurements were performed on anesthetized WT and Obscn KO 8-mo-old male mice, using a standardized protocol (Merx et al., 2014).”
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Butun, T. T., Özen, N., Öztürk, N., Yildirim, A. Ö., Kilavuz, E., Karadağ, C., Yüksel, B. A., Basralı, F., Karadağ, B., & Ülker, P. (2024) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365513.2024.2394982
Role of erythrocyte Gq protein in tumor metastasis
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- Authors
- Merx, M. W., Gorressen, S., Sandt, A. M., Cortese-Krott, M. M., Ohlig, J., Stern, M., Rassaf, T., Gödecke, A., Gladwin, M. T., & Kelm, M.
- Affiliations
- Düsseldorf University Hospital (DE)
- Heinrich Heine University Düsseldorf (DE)
- University of Pittsburgh (US)
- Corresponding author
- Merx, Marc W.
- ORCID
- Venue
- Basic Research in Cardiology
- Published
- 2013-12-18
- Volume
- 109
- Issue
- 1
- Pages
- 398-398
- ISSN
- 0003-9217 (ISSN-L)
- 0300-8428
- 1435-1803
- PMC
- PMC3898535
- OpenAlex
- W2067838633
- Cited by
- 53
- References
- 52
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 5 · 2016: 6 · 2015: 3 · 2014: 3
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Basic Research in Cardiology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL098032)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Keywords
- endothelial nitric oxide synthase, NOS3, myocardial infarction, myocardial ischemia-reperfusion injury, erythrocytes, nitrite/nitrate, erythrocyte deformability, infarct size, left ventricular dysfunction, bone marrow chimeras, nitric oxide signaling, vascular reactivity, nitric oxide donors
- MeSH terms
- Animals, Disease Models, Animal, Male, Mice, Inbred C57BL, Myocardial Infarction, Nitric Oxide, Blotting, Western, Myocardial Reperfusion Injury, Transplantation Chimera, Mice, Knockout, Ventricular Dysfunction, Left, Mice, Nitric Oxide Synthase Type III
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