Letter by Tziakas et al Regarding Article, “Aortic Valve Stenosis: From Basic Mechanisms to Novel Therapeutic Targets”

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 40, No. 6Letter by Tziakas et al Regarding Article, “Aortic Valve Stenosis: From Basic Mechanisms to Novel Therapeutic Targets” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Tziakas et al Regarding Article, “Aortic Valve Stenosis: From Basic Mechanisms to Novel Therapeutic Targets” Dimitrios N. Tziakas, Maria Pavlaki, Georgios Chalikias, Stavros V. Konstantinides and Katrin Schäfer Dimitrios N. TziakasDimitrios N. Tziakas From the Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece (D.N.T., M.P., G.C., S.V.K.) Search for more papers by this author , Maria PavlakiMaria Pavlaki From the Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece (D.N.T., M.P., G.C., S.V.K.) Search for more papers by this author , Georgios ChalikiasGeorgios Chalikias From the Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece (D.N.T., M.P., G.C., S.V.K.) Search for more papers by this author , Stavros V. KonstantinidesStavros V. Konstantinides From the Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece (D.N.T., M.P., G.C., S.V.K.) Center for Thrombosis and Hemostasis (S.V.K.), University Medical Center of the Johannes Gutenberg University Mainz, German. Search for more papers by this author and Katrin SchäferKatrin Schäfer Center for Cardiology, Cardiology I (K.S.), University Medical Center of the Johannes Gutenberg University Mainz, German. Search for more papers by this author Originally published27 May 2020https://doi.org/10.1161/ATVBAHA.120.314456Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:e180–e181To the Editor:The review article by Goody et al1 in the April issue of the Journal summarizes the current knowledge on the pathomechanisms of calcific aortic valve disease and refers to possible future treatment strategies. The authors elegantly describe the progression of the disease in the initiation and propagation phase. The former is characterized by lipid deposition, accompanied by injury and inflammation; in the latter, osteogenic differentiation and calcification are responsible for disease progression.1 However, the possible contribution of erythrocytes to vascular calcification and calcific aortic valve disease appears to have skipped the attention of the authors.Erythrocyte extravasation may occur during intraplaque hemorrhage in atherosclerosis or intraleaflet hemorrhage in calcific aortic valve disease. Indeed, intraleaflet hemorrhage was shown to be associated with the severity and progression of degenerative aortic valve stenosis.2 Recently, our group reported that erythrocyte membranes, but not intact red cells, promoted calcification of human arterial smooth muscle cells in culture.3 This effect was mediated by an increased expression of osteoblast-specific transcription factors (runt-related transcription factor 2, osterix) and differentiation markers (osteopontin, osteocalcin, and osterix). We further found that erythrocyte membranes dose dependently enhanced calcification in murine aortic rings ex vivo and observed extravasated erythrocytes colocalizing with calcified areas or osteoblast-like cells by analyzing human vascular lesions. A series of in vitro experiments revealed that the osteoinductive activity of lysed erythrocytes did not involve membrane lipids, heme, or iron; instead, it was mediated by nitric oxide–dependent intracellular pathways.3 The role of nitric oxide in the regulation of osteogenesis has recently been reviewed,4 and erythrocytes have been shown to express eNOS (endothelial nitric oxide synthase) localized at the cytoplasmic side of the red blood cell membrane.5,6 In our studies, erythrocytes isolated from endothelial eNOS-deficient mice exhibited a reduced potency to promote calcification in the aortic ring assay ex vivo and after injection into murine vascular lesions in vivo.3 Taken together, the results of our group and others indicate that intraleaflet/intraplaque hemorrhage with erythrocyte extravasation and lysis may promote osteoblastic differentiation of smooth muscle cells and vascular lesion calcification. They complement the findings of other groups that reported a role of red blood cells in modulating inflammatory cell function and vascular lesion progression.7,8DisclosuresNone.FootnotesFor Disclosures, see page e180.References1. Goody PR, Hosen MR, Christmann D, Niepmann ST, Zietzer A, Adam M, Bönner F, Zimmer S, Nickenig G, Jansen F. Aortic valve stenosis: from basic mechanisms to novel therapeutic targets.Arterioscler Thromb Vasc Biol. 2020; 40:885–900. doi: 10.1161/ATVBAHA.119.313067LinkGoogle Scholar2. Akahori H, Tsujino T, Naito Y, Matsumoto M, Lee-Kawabata M, Ohyanagi M, Mitsuno M, Miyamoto Y, Daimon T, Hao H, et al. Intraleaflet haemorrhage is associated with rapid progression of degenerative aortic valve stenosis.Eur Heart J. 2011; 32:888–896. doi: 10.1093/eurheartj/ehq479CrossrefMedlineGoogle Scholar3. Tziakas DN, Chalikias G, Pavlaki M, Kareli D, Gogiraju R, Hubert A, Böhm E, Stamoulis P, Drosos I, Kikas P, et al. Lysed erythrocyte membranes promote vascular calcification.Circulation. 2019; 139:2032–2048. doi: 10.1161/CIRCULATIONAHA.118.037166LinkGoogle Scholar4. Kalyanaraman H, Schall N, Pilz RB. Nitric oxide and cyclic GMP functions in bone.Nitric Oxide. 2018; 76:62–70. doi: 10.1016/j.niox.2018.03.007CrossrefMedlineGoogle Scholar5. Cortese-Krott MM, Rodriguez-Mateos A, Sansone R, Kuhnle GG, Thasian-Sivarajah S, Krenz T, Horn P, Krisp C, Wolters D, Heiß C, et al. Human red blood cells at work: identification and visualization of erythrocytic eNOS activity in health and disease.Blood. 2012; 120:4229–4237. doi: 10.1182/blood-2012-07-442277CrossrefMedlineGoogle Scholar6. Kleinbongard P, Schulz R, Rassaf T, Lauer T, Dejam A, Jax T, Kumara I, Gharini P, Kabanova S, Ozüyaman B, et al. Red blood cells express a functional endothelial nitric oxide synthase.Blood. 2006; 107:2943–2951. doi: 10.1182/blood-2005-10-3992CrossrefMedlineGoogle Scholar7. Cornelissen A, Guo L, Sakamoto A, Virmani R, Finn AV. New insights into the role of iron in inflammation and atherosclerosis.EBioMedicine. 2019; 47:598–606. doi: 10.1016/j.ebiom.2019.08.014CrossrefMedlineGoogle Scholar8. Delbosc S, Bayles RG, Laschet J, Ollivier V, Ho-Tin-Noé B, Touat Z, Deschildre C, Morvan M, Louedec L, Gouya L, et al. Erythrocyte efferocytosis by the arterial wall promotes oxidation in early-stage atheroma in humans.Front Cardiovasc Med. 2017; 4:43. doi: 10.3389/fcvm.2017.00043CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails June 2020Vol 40, Issue 6 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.120.314456PMID: 32459539 Originally publishedMay 27, 2020 PDF download Advertisement SubjectsEndothelium/Vascular Type/Nitric OxideMechanismsSmooth Muscle Proliferation and DifferentiationValvular Heart DiseaseVascular Biology