Protective Role of GPER Agonist G-1 on Cardiotoxicity Induced by Doxorubicin.
The use of Doxorubicin (Dox), a frontline drug for many cancers, is often complicated by dose-limiting cardiotoxicity in approximately 20% of patients. The G-protein estrogen receptor GPER/GPR30 mediates estrogen action as the cardioprotection under certain stressful conditions. For instance, GPER activation by the selective agonist G-1 reduced myocardial inflammation, improved immunosuppression, triggered pro-survival signaling cascades, improved myocardial mechanical performance, and reduced infarct size after ischemia/reperfusion (I/R) injury. Hence, we evaluated whether ligand-activated GPER may exert cardioprotection in male rats chronically treated with Dox. 1 week of G-1 (50 μg/kg/day) intraperitoneal administration mitigated Dox (3 mg/kg/day) adverse effects, as revealed by reduced TNF-α, IL-1β, LDH, and ROS levels. Western blotting analysis of cardiac homogenates indicated that G-1 prevents the increase in p-c-jun, BAX, CTGF, iNOS, and COX2 expression induced by Dox. Moreover, the activation of GPER rescued the inhibitory action elicited by Dox on the expression of BCL2, pERK, and pAKT. TUNEL assay indicated that GPER activation may also attenuate the cardiomyocyte apoptosis upon Dox exposure. Using ex vivo Langendorff perfused heart technique, we also found an increased systolic recovery and a reduction of both infarct size and LDH levels in rats treated with G-1 in combination with Dox respect to animals treated with Dox alone. Accordingly, the beneficial effects induced by G-1 were abrogated in the presence of the GPER selective antagonist G15. These data suggest that GPER activation mitigates Dox-induced cardiotoxicity, thus proposing GPER as a novel pharmacological target to limit the detrimental cardiac effects of Dox treatment. J. Cell. Physiol. 232: 1640-1649, 2017. © 2016 Wiley Periodicals, Inc.
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
Ernestina M
EM
De Francesco
Department of Biology, Ecology, and E.S., University of Calabria, Rende (CS), Italy.
Carmine
C
Rocca
Department of Biology, Ecology, and E.S., University of Calabria, Rende (CS), Italy.
Francesco
F
Scavello
Department of Biology, Ecology, and E.S., University of Calabria, Rende (CS), Italy.
Daniela
D
Amelio
Department of Biology, Ecology, and E.S., University of Calabria, Rende (CS), Italy.
Teresa
T
Pasqua
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
Damiano C
DC
Rigiracciolo
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
Andrea
A
Scarpelli
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
Silvia
S
Avino
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
Francesca
F
Cirillo
Department of Experimental and Clinical Medicine, University of Catanzaro Magna Graecia, Catanzaro, Italy.
Nicola
N
Amodio
Department of Biology, Ecology, and E.S., University of Calabria, Rende (CS), Italy.|National Institute of Cardiovascular Research, Bologna, Italy.
Maria C
MC
Cerra
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
Marcello
M
Maggiolini
Department of Biology, Ecology, and E.S., University of Calabria, Rende (CS), Italy.|National Institute of Cardiovascular Research, Bologna, Italy.
Tommaso
T
Angelone
D000818:Animals; D006801:Humans; D008297:Male; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D066126:Cardiotoxicity / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D003971:Diastole / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects; D006334:Heart Function Tests / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D053583:Interleukin-1beta / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008024:Ligands; D017202:Myocardial Ischemia / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000097:blood; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D016276:Ventricular Function / Q000187:drug effects; D003517:Cyclopentanes
D015415:Biomarkers; D002316:Cardiotonic Agents; D004317:Doxorubicin; C520305:Gper1 protein, rat; D053583:Interleukin-1beta; D007770:L-Lactate Dehydrogenase; D008024:Ligands; D011804:Quinolines; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D003517:Cyclopentanes