Enterovirus-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis.
OBJECTIVE
We examined the impact of enterovirus (EV) cardiac replication activity on the endomyocardial mitochondrial pathway in patients with acute myocarditis.


RESULTS
Levels of apoptotic cardiomyocytes were determined by TUNEL and ligation-mediated polymerase chain reaction (PCR) assays and EV replication activity was assessed by immunostaining of EV VP1 capsid protein in ventricular myocytes of patients with acute myocarditis (n = 25), and healthy heart controls (n = 15). Ratio of cytosolic/mitochondrial cytochrome c concentrations was determined by ELISA assay, levels of active caspase-9 were determined by western blot analysis and Bax/Bcl2 mRNA ratio was assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR) in the same cardiac tissues. Patients with EV-associated acute myocarditis (n = 15) exhibited a significantly higher number of apoptotic cardiomyocytes than those with non-EV-associated acute myocarditis (n = 10) and controls (n = 15) (P < 0.001). Endomyocardial ratio of cytosolic/mitochondrial cytochrome c concentrations and levels of active caspase-9 protein were significantly increased in EV than in non-EV-related myocarditis patients (P < 0.001). Moreover, Bax/Bcl2 mRNA ratio was significantly increased in EV than in non-EV-related myocarditis patients (P < 0.001).


CONCLUSIONS
Our findings evidence an EV-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis. Moreover, our results indicate that this EV-induced pro-apoptotic mechanism could be partly related to an up-regulation of Bax expression, and suggest that inhibition of this cell death process may constitute the basis for novel therapies.
Ventéo
Lydie
L
Laboratoire de Virologie médicale et moléculaire Hôpital Robert Debré, IFR 53/EA4303, CHU et Faculté de Médecine de Reims, Avenue du Général Koenig, 51092 REIMS Cedex, France.
Bourlet
Thomas
T
Renois
Fanny
F
Douche-Aourik
Fatima
F
Mosnier
Jean-François
JF
Maison
Geoffroy Lorain De la Grand
GL
Pluot
Michel
M
Pozzetto
Bruno
B
Andreoletti
Laurent
L
D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000502:physiology*; D016022:Case-Control Studies; D053453:Caspase 9 / Q000378:metabolism; D002472:Cell Transformation, Viral; D045305:Cytochromes c' / Q000378:metabolism; D004279:DNA, Viral / Q000032:analysis; D004769:Enterovirus Infections; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000821:virology*; D009205:Myocarditis / Q000821:virology*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000821:virology*; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000032:analysis; D014760:Viral Fusion Proteins / Q000378:metabolism; D055815:Young Adult
D045305:Cytochromes c'; D004279:DNA, Viral; D012333:RNA, Messenger; D012367:RNA, Viral; D014760:Viral Fusion Proteins; D053453:Caspase 9