期刊
JOURNAL OF PHARMACOLOGICAL SCIENCES
卷 109, 期 3, 页码 354-359出版社
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1254/jphs.08R26FM
关键词
cardiac adenylyl cyclase; knockout mouse; autonomic nervous system; heart failure; longevity; cardiac disease
资金
- National Institutes of Health [GM067773]
- American Heart Association [0020323U]
- Japanese Ministry of Education, Culture, Sports, Science, and Technology
- Japan Space Forum
- Kitsuen Kagaku Research Foundation
- Fukuda Foundation for Medical Technology
- Takeda Science Foundation
- Kimura Memorial Foundation/Pfizer Pharmaceuticals
- Yokohama Foundation for Advancement of Medical Science
- Yokohama City University, Japan [K19027]
- Mitsubishi Pharma Research Foundation
- Yokohama Academic Foundation
- Research for Promoting Technological Seeds
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM067773] Funding Source: NIH RePORTER
Cyclic AMP (cAMP) is known to play a major role in regulating cardiac function. Difference in adenylyl cyclase (AC) isoforms is a potential mechanism by which the cAMP signal, a common second messenger signal, can be regulated in a tissue-specific manner. However, the physiological significance of expressing multiple AC isoforms in a tissue and how each specific isoform regulates the cAMP signal remains poorly understood. In a genetically engineered mouse model in which the expression of the type 5 AC is knocked out (AC5KO), we identified the attenuation of autonomic regulation and calcium-mediated inhibition of cardiac function. We also identified that disruption of type 5 AC preserves cardiac function in response to chronic pressure-overload and catecholamine stress, at least in part, through the inhibition of cardiac apoptosis, which plays a major role in the development of heart failure. The protection against both apoptosis and development of cardiac dysfunction induced by left ventricular pressure overload in AC5KO makes this molecule potentially important for developing future pharmacotherapy, where suppressing the activity of type 5 AC, and not the entire beta-adrenergic signaling (beta-AR) signaling pathway, may have an advantage over the current beta-AR-blockade therapy in the treatment of heart failure.
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