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: Kosaku Iwatsubo, Claudio Bravo, Masami Uechi, Erdene Baljinnyam, Takashi Nakamura, Masanari Umemura, Lo Lai, Shumin Gao, Lin Yan, Xin Zhao, Misun Park, Hongyu Qiu, Satoshi Okumura, Mizuka Iwatsubo, Dorothy E Vatner, Stephen F Vatner, Yoshihiro Ishikawa
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 302 Issue 12 Pg. H2622-8 (Jun 15 2012) ISSN: 1522-1539 [Electronic] United States
• PMID: 22505646 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adenylyl Cyclase Inhibitors
• Antiviral Agents
• Extracellular Signal-Regulated MAP Kinases
• Adenylyl Cyclases
• adenylyl cyclase type V
• Vidarabine

Topics

• Adenylyl Cyclase Inhibitors
• Adenylyl Cyclases (metabolism)
• Animals
• Antiviral Agents (pharmacology, therapeutic use)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Heart (drug effects, physiopathology)
• Heart Failure (metabolism, physiopathology, prevention & control)
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Transgenic
• Myocardium (metabolism)
• Vidarabine (pharmacology, therapeutic use)