期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 302, 期 12, 页码 H2622-H2628出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00190.2012
关键词
heart failure; type 5 adenylyl cyclase inhibition; adenine 9-beta-D-arabinofuranoside
资金
- American Heart Association [SDG 0835596D]
- University of Medicine and Dentistry of New Jersey
- Melanoma Research Foundation
- Japanese Ministry of Health Labor and Welfare
- National Institutes of Health [GM-067773, HL-102472, AG-027211, HL-033107, HL-059139, HL-069752, HL-095888, HL-069020, HL-58960, HL-062863, AG-023137, AG-014121, AG-023567]
- [22136009]
- Grants-in-Aid for Scientific Research [23591087, 24390200, 22136009] Funding Source: KAKEN
Iwatsubo K, Bravo C, Uechi M, Baljinnyam E, Nakamura T, Umemura M, Lai L, Gao S, Yan L, Zhao X, Park M, Qiu H, Okumura S, Iwatsubo M, Vatner DE, Vatner SF, Ishikawa Y. Prevention of heart failure in mice by an antiviral agent that inhibits type 5 cardiac adenylyl cyclase. Am J Physiol Heart Circ Physiol 302: H2622-H2628, 2012. First published April 13, 2012; doi:10.1152/ajpheart.00190.2012.-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-beta-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.
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