Ranolazine protects from doxorubicin-induced oxidative stress and cardiac dysfunction.
OBJECTIVE
Doxorubicin is widely used against cancer; however, it can produce heart failure (HF). Among other hallmarks, oxidative stress is a major contributor to HF pathophysiology. The late INa inhibitor ranolazine has proven effective in treating experimental HF. Since elevated [Na+]i is present in failing myocytes, and has been recently linked with reactive oxygen species (ROS) production, our aim was to assess whether ranolazine prevents doxorubicin-induced cardiotoxicity, and whether blunted oxidative stress is a mechanism accounting for such protection.


RESULTS
In C57BL6 mice, doxorubicin treatment for 7 days produced LV dilation and decreased echo-measured fractional shortening (FS). Ranolazine (305 mg/kg/day) prevented LV dilation and dysfunction when co-administered with doxorubicin. Doxorubicin-induced cardiotoxicity was accompanied instead by elevations in atrial natriuretic peptide (ANP), BNP, connective tissue growth factor (CTGF), and matrix metalloproteinase 2 (MMP2) mRNAs, which were not elevated on co-treatment with ranolazine. Alterations in extracellular matrix remodelling were confirmed by an increase in interstitial collagen, which did not rise in ranolazine-co-treated hearts. Levels of poly(ADP-ribose) polymerase (PARP) and pro-caspase-3 measured by western blotting were lowered with doxorubicin, with increased cleavage of caspase-3, indicating activation of the proapoptotic machinery. Again, ranolazine prevented this activation. Furthermore, in HL-1 cardiomyocytes transfected with HyPer to monitor H2O2 emission, besides reducing the extent of cell death, ranolazine prevented the occurrence of oxidative stress caused by doxorubicin. Interestingly, similar protective results were obtained with the Na+/Ca2+ exchanger (NCX) inhibitor KB-R7943.


CONCLUSIONS
Ranolazine protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by a reduction in oxidative stress, suggesting that INa modulates cardiac redox balance, resulting in functional and morphological derangements.
Carlo G
CG
Tocchetti
Andrea
A
Carpi
Carmela
C
Coppola
Cristina
C
Quintavalle
Domenica
D
Rea
Marika
M
Campesan
Antonella
A
Arcari
Giovanna
G
Piscopo
Clemente
C
Cipresso
Maria Gaia
MG
Monti
Claudia
C
De Lorenzo
Claudio
C
Arra
Gerolama
G
Condorelli
Fabio
F
Di Lisa
Nicola
N
Maurea
D000083:Acetanilides / Q000627:therapeutic use*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D009320:Atrial Natriuretic Factor / Q000235:genetics; D015153:Blotting, Western / Q000379:methods; D066126:Cardiotoxicity / Q000000981:diagnostic imaging / Q000517:prevention & control; D055513:Connective Tissue Growth Factor / Q000235:genetics; D004317:Doxorubicin / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D000069458:Ranolazine; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012964:Sodium / Q000097:blood; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
D000083:Acetanilides; D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D010879:Piperazines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D020097:Natriuretic Peptide, Brain; D055513:Connective Tissue Growth Factor; D004317:Doxorubicin; D009320:Atrial Natriuretic Factor; D012964:Sodium; D000069458:Ranolazine; D011065:Poly(ADP-ribose) Polymerases; D020778:Matrix Metalloproteinase 2