MICE GENETICALLY LACKING NRF2 DEVELOP AGE DEPENDENT CARDIOMYOPATHY
Enrica Federti1, Iana Iatcenko1, Serge Cedrick Mbiandjeu Toya1, Francesca Vinchi2, Alessandro Matte'1,
Alessandra Ghigo3, Angela Siciliano1, Deborah Chiabrando3, Emanuela Tolosano3, Veronica Riccardi1,
Roberta Russo4, Immacolata Andolfo4, Achille Iolascon4 and Lucia De Franceschi1
(1)Department of Medicine, University of Verona and AOUI Verona, Verona, Italy
(2)Iron Research Program, Lindsley Kimball Research Institute and New York Blood Center, New York
(NY)
(3)Department Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center,
University of Torino, Turin, Italy, (4)Deprtment of Molecular Medicine and Medical Biotechnologies,
Federico II University of Naples and CEINGE - Biotecnologie Avanzate, Naples, Italy
Cardiomyopathy due to iron-overload is a severe complication of patients undergoing to
chronic transfusion regimen such as b-thalassemia or myelodysplastic syndromes. Previous
studies have shown the key role of Nrf2, a redox related transcriptional factor, in both b-thalassemic
erythropoiesis and iron homeostasis (Matte A et al. ARS 2018, 2019; Lim PJ et al
Nat Metab, 2019). Here, we studied Nrf2 knockout male mice (Nrf2-/-) and C57BL-6J as wild-type
(WT) controls. Nrf2-/- mice are characterized by mild chronic hemolytic anemia
associated with ineffective erythropoiesis, similar to that observed in murine b-thalassemia
(Toya SCM et al., Blood, 2019).
Aged Nrf2-/- mice developed diastolic dysfunction and reduced cardiac performance when
compared to WT animals. In heart from Nrf2-/- mice, Pearls staining revealed cardiac iron
accumulation when compared to WT animals. This was associated with higher plasma NTBI
than in WT mice. Nrf2-/- murine cardiomyopathy was characterized by (i) increased heart
protein oxidation; (ii) reduced expression of Nrf2 dependent antioxidant systems such as
NQO1, SOD1 and catalase; (iii) activation of redox related transcriptional factors such as NF-kB
and STAT3. We then explored whether the increased pro-oxidant environment observed
in Nrf2-/- murine cardiomyopathy might affect Ca2+ dependent SERCA2A expression.
SERCA2A plays a key role in the pathogenesis of different cardiomyopathies such as
hypertrophic cardiomyopathy or chronic heart failure. In Nrf2-/-mice, we found degradation
of SERCA2A and the presence of proteolytic products. This was associated with increased
activity of metalloprotease 9 that has been involved in both SERCA2A degradation and heart
remodelling.
Our data supports the crucial role of Nrf2 against oxidation induced by aging. Further studies
are required to better characterize the link between myocardial dysfunction and Nrf2 in
different models such as in cardiomyopathy associated with b-thalassemia.
POSTER 5
SCIENTIFIC PROGRAMME
SESSION I
BONE MARROW
RESPONSE TO VIRAL
INFECTIONS
SESSION II
HAEMATOLOGICAL
RESPONSE TO SARS
COV2 INFECTION
SESSION III
DYSERYTHROPOIESIS IN
CLONAL HAEMOPOIESIS
AND MDS
SESSION IV
ERYTHROPOIESIS
CONTROL
SESSION V
ERYTHROPOIESIS
CONTROL : PHASE 2
SESSION VI
IRON METABOLISM
AND ERYTHROPOIESIS
SESSION VII
INHERITED
DYSERYTHROPOIESIS
SESSION VIII
GENE THERAPY/EDITION
SESSION IX – DRUGS
AND INEFFECTIVE
ERYTHROPOIESIS
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FOR A POSTER
PRESENTATION
FACULTY DISCLOSURES