New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Effects of Targeted Disruption of the Type 5 Adenylyl Cyclase Gene

Journal of Pharmacological Sciences

Yoshihiro Ishikawa¹  Sayaka Suzuki¹  Satoshi Okumura¹ 

[1] Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Japan

关键词: cardiac adenylyl cyclase;    knockout mouse;    autonomic nervous system;    heart failure;    longevity;    cardiac disease;   

DOI  :  10.1254/jphs.08R26FM

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(23)Cited-By(12)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 β-adrenergic signaling (β-AR) signaling pathway, may have an advantage over the current β-AR–blockade therapy in the treatment of heart failure.

【 授权许可】

Unknown