Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload.
The sympathetic nervous system is designed to respond to stress. Adenylyl cyclase (AC) is the keystone of sympathetic transmission, yet its role in response to acute overload in the heart or in the pathogenesis of heart failure is controversial. We examined the effects of pressure overload, induced by thoracic aortic banding, in mice in which type 5 AC, a major cardiac AC isoform, was disrupted (AC5-/-). Left ventricular weight/tibial length ratio (LVW/TL) was not different between the WT and AC5-/- at baseline and increased progressively and similarly in both groups at 1 and 3 wk after aortic banding. However, LV ejection fraction (LVEF) fell in WT at 3 wk after banding (from 70 +/- 2.8 to 57 +/- 3.9%, P < 0.05), and this decrease was associated with LV dilatation, indicating incipient cardiac failure. In contrast, AC5-/- mice did not exhibit a fall in LVEF from 74 +/- 2.2%. The number of apoptotic myocytes was similar at baseline, but it increased roughly 4-fold in WT at both 1 and 3 wk after banding, and significantly less, P < 0.05, in AC5-/-. Importantly, the increase in apoptosis occurred before the decline in LVEF in WT. The protective mechanism seems to involve Bcl-2, which was up-regulated significantly more in AC5-/- mice with pressure overload. Our findings suggest that limiting type 5 AC plays a protective role in response to pressure overload and the development of heart failure, potentially through limiting the incidence of myocardial apoptosis.
Okumura
Satoshi
S
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine and Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07101-1709, USA.
Takagi
Gen
G
Kawabe
Jun-ichi
J
Yang
Guiping
G
Lee
Ming-Chih
MC
Hong
Chull
C
Liu
Jing
J
Vatner
Dorothy E
DE
Sadoshima
Junichi
J
Vatner
Stephen F
SF
Ishikawa
Yoshihiro
Y
D000262:Adenylyl Cyclases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000209:etiology; D004195:Disease Models, Animal; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D016277:Ventricular Function, Left
D007527:Isoenzymes; D019253:Proto-Oncogene Proteins c-bcl-2; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V