Cardioprotective potential of oleuropein, hydroxytyrosol, oleocanthal and their combination: Unravelling complementary effects on acute myocardial infarction and metabolic syndrome
Andriana Christodoulou,
Panagiota-Efstathia Nikolaou,
Lydia Symeonidi,
Konstantinos Katogiannis,
Louisa Pechlivani,
Theodora Nikou,
Aimilia Varela,
Christina Chania,
Stelios Zerikiotis,
Panagiotis Efentakis,
Dimitris Vlachodimitropoulos,
Nikolaos Katsoulas,
Anna Agapaki,
Costantinos Dimitriou,
Maria Tsoumani,
Nikolaos Kostomitsopoulos,
Constantinos H. Davos,
Alexios Leandros Skaltsounis,
Alexandros Tselepis,
Maria Halabalaki,
Ioulia Tseti,
Efstathios K. Iliodromitis,
Ignatios Ikonomidis,
Ioanna Andreadou
Affiliations
Andriana Christodoulou
Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Zografou, Athens, Greece
Panagiota-Efstathia Nikolaou
Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Zografou, Athens, Greece
Lydia Symeonidi
Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Zografou, Athens, Greece
Konstantinos Katogiannis
Laboratory of Echocardiography and Preventive Cardiology, Second Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
Louisa Pechlivani
Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece
Theodora Nikou
Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
Aimilia Varela
Cardiovascular Research Laboratory, Biomedical Research Foundation Academy of Athens (BRFAA), Athens, Greece
Christina Chania
Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Zografou, Athens, Greece
Stelios Zerikiotis
Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Zografou, Athens, Greece
Panagiotis Efentakis
Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Zografou, Athens, Greece
Dimitris Vlachodimitropoulos
Laboratory of Forensic Medicine and Toxicology, Medical School National and Kapodistrian University of Athens, Athens, Greece
Nikolaos Katsoulas
Laboratory of Forensic Medicine and Toxicology, Medical School National and Kapodistrian University of Athens, Athens, Greece
Anna Agapaki
Histochemistry Unit, Biomedical Research Foundation, Academy of Athens (BRFAA), Athens, Greece
Costantinos Dimitriou
Centre of Clinical Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
Maria Tsoumani
Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Zografou, Athens, Greece
Nikolaos Kostomitsopoulos
Centre of Clinical Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
Constantinos H. Davos
Cardiovascular Research Laboratory, Biomedical Research Foundation Academy of Athens (BRFAA), Athens, Greece
Alexios Leandros Skaltsounis
Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
Alexandros Tselepis
Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece
Maria Halabalaki
Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
Ioulia Tseti
Uni-Pharma S.A., Athens, Greece
Efstathios K. Iliodromitis
National and Kapodistrian University of Athens, Medical School, Athens, Greece
Ignatios Ikonomidis
Laboratory of Echocardiography and Preventive Cardiology, Second Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
Ioanna Andreadou
Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Zografou, Athens, Greece; Corresponding author. Laboratory of Pharmacology, Faculty of Pharmacy, Panepistimiopolis, Zografou, Athens, 15771, Greece.
Clinical studies have previously established the role of olive products in cardiovascular disease (CVD) prevention, whilst the identification of the responsible constituents for the beneficial effects is still pending. We sought to assess and compare the cardioprotective potential of oleuropein (OL), hydroxytyrosol (HT), oleocanthal (OC) and oleanolic Acid (OA), regarding Ischemia/Reperfusion Injury (IRI) and CVD risk factors alleviation. The scope of the study was to design a potent and safe combinatorial therapy for high-cardiovascular-risk patients on a bench-to-bedside approach. We evaluated the IRI-limiting potential of 6-weeks treatment with OL, HT, OC or OA at nutritional doses, in healthy and metabolic syndrome (MS)-burdened mice. Three combinatorial regimens were designed and the mixture with preponderant benefits (OL-HT-OC, Combo 2), including infarct sparing and antiglycemic potency, compared to the isolated compounds, was further investigated for its anti-atherosclerotic effects. In vivo experiments revealed that the combination regimen of Combo 2 presented the most favorable effects in limiting infarct size and hyperglycemia, which was selected to be further investigated in the clinical setting in Chronic Coronary Artery Syndrome (CCAS) patients. Cardiac function, inflammation markers and oxidative stress were assessed at baseline and after 4 weeks of treatment with the OL-HT-OC supplement in the clinical study. We found that OL, OC and OA significantly reduced infarct size in vivo compared to Controls. OL exhibited antihyperglycemic properties and OA attenuated hypercholesterolemia. OL-HT-OA, OL-HT-OC and OL-HT-OC-OA combination regimens were cardioprotective, whereas only OL-HT-OC mitigated hyperglycemia. Combo 2 cardioprotection was attributed to apoptosis suppression, enhanced antioxidant effects and upregulation of antioxidant enzymes. Additionally, it reduced atherosclerotic plaque extent in vivo. OL-HT-OC supplement ameliorated cardiac, vascular and endothelial function in the small-scale clinical study. Conclusively, OL-HT-OC combination therapy exerts potent cardioprotective, antihyperglycemic and anti-atherosclerotic properties in vivo, with remarkable and clinically translatable cardiovascular benefits in high-risk patients.
