Cardiac-specific overexpression of catalase identifies hydrogen peroxide-dependent and -independent phases of myocardial remodeling and prevents the progression to overt heart failure in G(alpha)q-overexpressing transgenic mice.
BACKGROUND
Although it seems that reactive oxygen species contribute to chronic myocardial remodeling, questions remain about (1) the specific types of reactive oxygen species involved, (2) the role of reactive oxygen species in mediating specific cellular events, and (3) the cause-and-effect relationship between myocardial reactive oxygen species and the progression to heart failure. Transgenic mice with myocyte-specific overexpression of G(alpha)q develop a dilated cardiomyopathy that progresses to heart failure. We used this model to examine the role of H(2)O(2) in mediating myocardial remodeling and the progression to failure.


RESULTS
In G(alpha)q myocardium, markers of oxidative stress were increased at 4 weeks and increased further at 20 weeks. G(alpha)q mice were crossbred with transgenic mice having myocyte-specific overexpression of catalase. At 4 weeks of age, left ventricular end-diastolic dimension was increased and left ventricular fractional shortening decreased in G(alpha)q mice and deteriorated further through 20 weeks. In G(alpha)q mice, myocardial catalase overexpression had no effect on left ventricular end-diastolic dimension or fractional shortening at 4 weeks but prevented the subsequent deterioration in both. In G(alpha)q mice, myocyte hypertrophy; myocyte apoptosis; interstitial fibrosis; and the progression to overt heart failure, as reflected by lung congestion and exercise intolerance, were prevented by catalase overexpression.


CONCLUSIONS
In G(alpha)q mice, myocyte-specific overexpression of catalase had no effect on the initial phenotype of left ventricular dilation and contractile dysfunction but prevented the subsequent progressive remodeling phase leading to heart failure. Catalase prevented the cellular hallmarks of adverse remodeling (myocyte hypertrophy, myocyte apoptosis, and interstitial fibrosis) and the progression to overt heart failure. Thus, H(2)O(2), associated oxidant pathways, or both play a critical role in adverse myocardial remodeling and the progression to failure.
Qin
Fuzhong
F
Cardiovascular Medicine Section and Myocardial Biology Unit, Boston University Medical Center, Boston, Mass 02118, USA.
Lennon-Edwards
Shannon
S
Lancel
Steve
S
Biolo
Andreia
A
Siwik
Deborah A
DA
Pimentel
David R
DR
Dorn
Gerald W
GW
Kang
Y James
YJ
Colucci
Wilson S
WS
D000704:Analysis of Variance; D000818:Animals; D002374:Catalase / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D019204:GTP-Binding Proteins / Q000378:metabolism; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology* / Q000517:prevention & control*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology*; D018384:Oxidative Stress; D010641:Phenotype; D015398:Signal Transduction; D020257:Ventricular Remodeling
D006861:Hydrogen Peroxide; D002374:Catalase; D019204:GTP-Binding Proteins