title: Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload.
abstract: 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.
authors.affiliation: 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.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
authors.forename: Gen
authors.initials: G
authors.lastname: Takagi
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kawabe
authors.forename: Guiping
authors.initials: G
authors.lastname: Yang
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Lee
authors.forename: Chull
authors.initials: C
authors.lastname: Hong
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: 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
chemical_list: D007527:Isoenzymes; D019253:Proto-Oncogene Proteins c-bcl-2; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V