Early microvascular coronary endothelial dysfunction precedes pembrolizumab-induced cardiotoxicity. Preventive role of high dose of atorvastatin

2024
journal article
article
dc.abstract.enImmune checkpoint inhibitors (ICIs) exhibit remarkable antitumor activity and immune-related cardiotoxicity of unknown pathomechanism. The aim of the study was to investigate the ICI class-dependent cardiotoxicity in vitro and pembrolizumab's (Pem's) cardiotoxicity in vivo, seeking for translational prevention means. Cytotoxicity was investigated in primary cardiomyocytes and splenocytes, incubated with ipilimumab, Pem and avelumab. Pem’s cross-reactivity was assessed by circular dichroism (CD) on biotechnologically produced human and murine PD-1 and in silico. C57BL6/J male mice received IgG4 or Pem for 2 and 5 weeks. Echocardiography, histology, and molecular analyses were performed. Coronary blood flow velocity mapping and cardiac magnetic resonance imaging were conducted at 2 weeks. Human EA.hy926 endothelial cells were incubated with Pem-conditioned media from human mononuclear cells, in presence and absence of statins and viability and molecular signaling were assessed. Atorvastatin (20 mg/kg, daily) was administered in vivo, as prophylaxis. Only Pem exerted immune-related cytotoxicity in vitro. Pem’s cross-reactivity with the murine PD-1 was confirmed by CD and docking. In vivo, Pem initiated coronary endothelial and diastolic dysfunction at 2 weeks and systolic dysfunction at 5 weeks. At 2 weeks, Pem induced ICAM-1 and iNOS expression and intracardiac leukocyte infiltration. At 5 weeks, Pem exacerbated endothelial activation and triggered cardiac inflammation. Pem led to immune-related cytotoxicity in EA.hy926 cells, which was prevented by atorvastatin. Atorvastatin mitigated functional deficits, by inhibiting endothelial dysfunction in vivo. We established for the first time an in vivo model of Pem-induced cardiotoxicity. Coronary endothelial dysfunction precedes Pem-induced cardiotoxicity, whereas atorvastatin emerges as a novel prophylactic therapy.pl
dc.affiliationWydział Lekarski : Zakład Farmakologiipl
dc.affiliationPion Prorektora ds. badań naukowych : Jagiellońskie Centrum Rozwoju Lekówpl
dc.cm.id114751
dc.cm.idOmegaUJCMeb2638aee34e42c884561ad57f3cb170pl
dc.contributor.authorEfentakis, Panagiotispl
dc.contributor.authorChoustoulaki, Angelikipl
dc.contributor.authorKwiatkowski, Grzegorz - 149211 pl
dc.contributor.authorVarela, Aimiliapl
dc.contributor.authorKostopoulos, Ioannis V.pl
dc.contributor.authorTsekenis, Georgepl
dc.contributor.authorNtanasis-Stathopoulos, Ioannispl
dc.contributor.authorGeorgoulis, Anastasiospl
dc.contributor.authorVorgias, Constantinos E.pl
dc.contributor.authorGakiopoulou, Harikleiapl
dc.contributor.authorBriasoulis, Alexandrospl
dc.contributor.authorDavos, Constantinos H.pl
dc.contributor.authorKostomitsopoulos, Nikolaospl
dc.contributor.authorTsitsilonis, Ouraniapl
dc.contributor.authorDimopoulos, Meletios A.pl
dc.contributor.authorTerpos, Evangelospl
dc.contributor.authorChłopicki, Stefan - 128995 pl
dc.contributor.authorGavriatopoulou, Mariapl
dc.contributor.authorAndreadou, Ioannapl
dc.date.accession2024-03-27pl
dc.date.accessioned2024-03-27T08:10:53Z
dc.date.available2024-03-27T08:10:53Z
dc.date.issued2024pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.additionalOnline First 2024-03-23pl
dc.description.physical[1-24]pl
dc.description.versionoryginalna wersja autorska (preprint)
dc.identifier.doi10.1007/s00395-024-01046-0pl
dc.identifier.eissn1435-1803pl
dc.identifier.issn0300-8428pl
dc.identifier.urihttps://ruj.uj.edu.pl/xmlui/handle/item/328505
dc.identifier.weblinkhttps://link.springer.com/article/10.1007/s00395-024-01046-0pl
dc.languageengpl
dc.language.containerengpl
dc.pbn.affiliationDziedzina nauk medycznych i nauk o zdrowiu : nauki medyczne
dc.rightsUdzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa*
dc.rights.licenceCC-BY
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/legalcode.pl*
dc.share.typeinne
dc.subject.enimmune checkpoint inhibitorspl
dc.subject.enpembrolizumabpl
dc.subject.enmicrovascular coronary endothelial dysfunctionpl
dc.subject.encardiotoxicitypl
dc.subject.enatorvastatinpl
dc.subject.encardio-oncologypl
dc.subtypeArticlepl
dc.titleEarly microvascular coronary endothelial dysfunction precedes pembrolizumab-induced cardiotoxicity. Preventive role of high dose of atorvastatinpl
dc.title.journalBasic Research in Cardiologypl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.enpl
Immune checkpoint inhibitors (ICIs) exhibit remarkable antitumor activity and immune-related cardiotoxicity of unknown pathomechanism. The aim of the study was to investigate the ICI class-dependent cardiotoxicity in vitro and pembrolizumab's (Pem's) cardiotoxicity in vivo, seeking for translational prevention means. Cytotoxicity was investigated in primary cardiomyocytes and splenocytes, incubated with ipilimumab, Pem and avelumab. Pem’s cross-reactivity was assessed by circular dichroism (CD) on biotechnologically produced human and murine PD-1 and in silico. C57BL6/J male mice received IgG4 or Pem for 2 and 5 weeks. Echocardiography, histology, and molecular analyses were performed. Coronary blood flow velocity mapping and cardiac magnetic resonance imaging were conducted at 2 weeks. Human EA.hy926 endothelial cells were incubated with Pem-conditioned media from human mononuclear cells, in presence and absence of statins and viability and molecular signaling were assessed. Atorvastatin (20 mg/kg, daily) was administered in vivo, as prophylaxis. Only Pem exerted immune-related cytotoxicity in vitro. Pem’s cross-reactivity with the murine PD-1 was confirmed by CD and docking. In vivo, Pem initiated coronary endothelial and diastolic dysfunction at 2 weeks and systolic dysfunction at 5 weeks. At 2 weeks, Pem induced ICAM-1 and iNOS expression and intracardiac leukocyte infiltration. At 5 weeks, Pem exacerbated endothelial activation and triggered cardiac inflammation. Pem led to immune-related cytotoxicity in EA.hy926 cells, which was prevented by atorvastatin. Atorvastatin mitigated functional deficits, by inhibiting endothelial dysfunction in vivo. We established for the first time an in vivo model of Pem-induced cardiotoxicity. Coronary endothelial dysfunction precedes Pem-induced cardiotoxicity, whereas atorvastatin emerges as a novel prophylactic therapy.
dc.affiliationpl
Wydział Lekarski : Zakład Farmakologii
dc.affiliationpl
Pion Prorektora ds. badań naukowych : Jagiellońskie Centrum Rozwoju Leków
dc.cm.id
114751
dc.cm.idOmegapl
UJCMeb2638aee34e42c884561ad57f3cb170
dc.contributor.authorpl
Efentakis, Panagiotis
dc.contributor.authorpl
Choustoulaki, Angeliki
dc.contributor.authorpl
Kwiatkowski, Grzegorz - 149211
dc.contributor.authorpl
Varela, Aimilia
dc.contributor.authorpl
Kostopoulos, Ioannis V.
dc.contributor.authorpl
Tsekenis, George
dc.contributor.authorpl
Ntanasis-Stathopoulos, Ioannis
dc.contributor.authorpl
Georgoulis, Anastasios
dc.contributor.authorpl
Vorgias, Constantinos E.
dc.contributor.authorpl
Gakiopoulou, Harikleia
dc.contributor.authorpl
Briasoulis, Alexandros
dc.contributor.authorpl
Davos, Constantinos H.
dc.contributor.authorpl
Kostomitsopoulos, Nikolaos
dc.contributor.authorpl
Tsitsilonis, Ourania
dc.contributor.authorpl
Dimopoulos, Meletios A.
dc.contributor.authorpl
Terpos, Evangelos
dc.contributor.authorpl
Chłopicki, Stefan - 128995
dc.contributor.authorpl
Gavriatopoulou, Maria
dc.contributor.authorpl
Andreadou, Ioanna
dc.date.accessionpl
2024-03-27
dc.date.accessioned
2024-03-27T08:10:53Z
dc.date.available
2024-03-27T08:10:53Z
dc.date.issuedpl
2024
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.additionalpl
Online First 2024-03-23
dc.description.physicalpl
[1-24]
dc.description.version
oryginalna wersja autorska (preprint)
dc.identifier.doipl
10.1007/s00395-024-01046-0
dc.identifier.eissnpl
1435-1803
dc.identifier.issnpl
0300-8428
dc.identifier.uri
https://ruj.uj.edu.pl/xmlui/handle/item/328505
dc.identifier.weblinkpl
https://link.springer.com/article/10.1007/s00395-024-01046-0
dc.languagepl
eng
dc.language.containerpl
eng
dc.pbn.affiliation
Dziedzina nauk medycznych i nauk o zdrowiu : nauki medyczne
dc.rights*
Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa
dc.rights.licence
CC-BY
dc.rights.uri*
http://creativecommons.org/licenses/by/4.0/legalcode.pl
dc.share.type
inne
dc.subject.enpl
immune checkpoint inhibitors
dc.subject.enpl
pembrolizumab
dc.subject.enpl
microvascular coronary endothelial dysfunction
dc.subject.enpl
cardiotoxicity
dc.subject.enpl
atorvastatin
dc.subject.enpl
cardio-oncology
dc.subtypepl
Article
dc.titlepl
Early microvascular coronary endothelial dysfunction precedes pembrolizumab-induced cardiotoxicity. Preventive role of high dose of atorvastatin
dc.title.journalpl
Basic Research in Cardiology
dc.typepl
JournalArticle
dspace.entity.type
Publication
Affiliations

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