Oleuropein prevents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism.
Oleuropein, a natural phenolic compound, prevents acute doxorubicin (DXR)-induced cardiotoxicity but there is no evidence regarding its role in chronic DXR-induced cardiomyopathy (DXR-CM). In the present study, we investigated the role of oleuropein in DXR-CM by addressing cardiac geometry and function (transthoracic echocardiography), cardiac histopathology, nitro-oxidative stress (MDA, PCs, NT), inflammatory cytokines (IL-6, Big ET-1), NO homeostasis (iNOS and eNOS expressions), kinases involved in apoptosis and metabolism (Akt, AMPK) and myocardial metabonomics. Rats were randomly divided into 6 groups: Control, OLEU-1 and OLEU-2 [oleuropein at 1000 and 2000 mg/kg in total, respectively, intraperitoneally (i.p.) for 14 days], DXR (18 mg/kg, i.p. divided into 6 equal doses for 2 weeks), DXR-OLEU-1 and DXR-OLEU-2 (both oleuropein and DXR as previously described). Impaired left ventricular contractility and inflammatory and degenerative pathology lesions were encountered only in the DXR group. The DXR group also had higher MDA, PCs, NT, IL-6 and Big ET-1 levels, higher iNOS and lower eNOS, Akt and AMPK activation compared to controls and the oleuropein-treated groups. Metabonomics depicted significant metabolite alterations in the DXR group suggesting perturbed energy metabolism and protein biosynthesis. The effectiveness of DXR in inhibiting cell proliferation is not compromised when oleuropein is present. We documented an imbalance between iNOS and eNOS expressions and a disturbed protein biosynthesis and metabolism in DXR-CM; these newly recognized pathways in DXR cardiotoxicity may help identifying novel therapeutic targets. Activation of AMPK and suppression of iNOS by oleuropein seem to prevent the structural, functional and histopathological cardiac effects of chronic DXR toxicity.
Department of Pharmaceutical Chemistry, University of Athens School of Pharmacy, Athens, Greece. Electronic address: jandread@pharm.uoa.gr.
Ioanna
I
Andreadou
Department of Pharmaceutical Chemistry, University of Athens School of Pharmacy, Athens, Greece. Electronic address: mikros@pharm.uoa.gr.
Emmanuel
E
Mikros
Department of Pharmaceutical Chemistry, University of Athens School of Pharmacy, Athens, Greece.
Konstantinos
K
Ioannidis
First Department of Surgery, University of Athens Medical School, Athens, Greece.
Fragiska
F
Sigala
Department of Cardiology, Michaelidion Cardiac Center, University of Ioannina, Ioannina, Greece.
Katerina
K
Naka
Department of Pharmaceutical Chemistry, University of Athens School of Pharmacy, Athens, Greece.
Sarantos
S
Kostidis
Second Department of Cardiology, University of Athens Medical School, Attikon University Hospital, Athens, Greece; First Department of Internal Medicine, University of Athens Medical School, Laiko Hospital, Athens, Greece.
Dimitrios
D
Farmakis
Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
Roxane
R
Tenta
Department of Pathology, University of Athens Medical School, Athens, Greece.
Nikolaos
N
Kavantzas
Department of Pharmaceutical Chemistry, University of Athens School of Pharmacy, Athens, Greece.
Sofia-Iris
SI
Bibli
Department of Pharmaceutical Chemistry, University of Athens School of Pharmacy, Athens, Greece.
Evangelos
E
Gikas
Department of Pharmaceutical Chemistry, University of Athens School of Pharmacy, Athens, Greece.
Leandros
L
Skaltsounis
Second Department of Cardiology, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
Dimitrios Th
DT
Kremastinos
Second Department of Cardiology, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
Efstathios K
EK
Iliodromitis
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D004452:Echocardiography; D004734:Energy Metabolism; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000378:metabolism; D057888:Iridoid Glucosides; D039823:Iridoids / Q000494:pharmacology*; D008297:Male; D055432:Metabolomics; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D015850:Interleukin-6; D057888:Iridoid Glucosides; D039823:Iridoids; D014665:Vasodilator Agents; C002769:oleuropein; D004317:Doxorubicin
Cardiomyopathy; Doxorubicin; Metabonomics; Oleuropein; Signaling molecules