title: Prevention of heart failure in mice by an antiviral agent that inhibits type 5 cardiac adenylyl cyclase.
abstract: Despite numerous discoveries from genetically engineered mice, relatively few have been translated to the bedside, mainly because it is difficult to translate from genes to drugs. This investigation examines an antiviral drug, which also has an action to selectively inhibit type 5 adenylyl cyclase (AC5), a pharmaceutical correlate of the AC5 knockout (KO) model, which exhibits longevity and stress resistance. Our objective was to examine the extent to which pretreatment with this drug, adenine 9-β-d-arabinofuranoside (Ara-A), favorably ameliorates the development of heart failure (HF). Ara-A exhibited selective inhibition for AC5 compared with the other major cardiac AC isoform, AC6, i.e., it reduced AC activity significantly in AC5 transgenic (Tg) mice, but not in AC5KO mice and had little effect in either wild-type or AC6Tg mice. Permanent coronary artery occlusion for 3 wk in C57Bl/6 mice increased mortality and induced HF in survivors, as reflected by reduced cardiac function, while increasing cardiac fibrosis. The AC5 inhibitor Ara-A significantly improved all of these end points and also ameliorated chronic isoproterenol-induced cardiomyopathy. As with the AC5KO mice, Ara-A increased mitogen/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation. A MEK inhibitor abolished the beneficial effects of the AC5 inhibitor in the HF model, indicating the involvement of the downstream MEK-ERK pathway of AC5. Our data suggest that pharmacological AC5 inhibition may serve as a new therapeutic approach for HF.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School-University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
authors.forename: Kosaku
authors.initials: K
authors.lastname: Iwatsubo
authors.forename: Claudio
authors.initials: C
authors.lastname: Bravo
authors.forename: Masami
authors.initials: M
authors.lastname: Uechi
authors.forename: Erdene
authors.initials: E
authors.lastname: Baljinnyam
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Masanari
authors.initials: M
authors.lastname: Umemura
authors.forename: Lo
authors.initials: L
authors.lastname: Lai
authors.forename: Shumin
authors.initials: S
authors.lastname: Gao
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Misun
authors.initials: M
authors.lastname: Park
authors.forename: Hongyu
authors.initials: H
authors.lastname: Qiu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
authors.forename: Mizuka
authors.initials: M
authors.lastname: Iwatsubo
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D014740:Vidarabine / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000998:Antiviral Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V; D014740:Vidarabine