Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function.

Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function. Research Abstract Details 

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Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function. Abstract Text:

Hajime Funakoshi,Tung O Chan,Julie C Good,Joseph R Libonati,Jarkko Piuhola,Xiongwen Chen,Scott M MacDonnell,Ling L Lee,David E Herrmann,Jin Zhang,Jeffrey Martini,Timothy M Palmer,Atsushi Sanbe,Jeffrey Robbins,Steven R Houser,Walter J Koch,Arthur M Feldman,

BACKGROUND: Both the A1- and A3-adenosine receptors (ARs) have been implicated in mediating the cardioprotective effects of adenosine. Paradoxically, overexpression of both A1-AR and A3-AR is associated with changes in the cardiac phenotype. To evaluate the temporal relationship between AR signaling and cardiac remodeling, we studied the effects of controlled overexpression of the A1-AR using a cardiac-specific and tetracycline-transactivating factor-regulated promoter. METHODS AND RESULTS: Constitutive A1-AR overexpression caused the development of cardiac dilatation and death within 6 to 12 weeks. These mice developed diminished ventricular function and decreased heart rate. In contrast, when A1-AR expression was delayed until 3 weeks of age, mice remained phenotypically normal at 6 weeks, and >90% of the mice survived at 30 weeks. However, late induction of A1-AR still caused mild cardiomyopathy at older ages (20 weeks) and accelerated cardiac hypertrophy and the development of dilatation after pressure overload. These changes were accompanied by gene expression changes associated with cardiomyopathy and fibrosis and by decreased Akt phosphorylation. Discontinuation of A1-AR induction mitigated cardiac dysfunction and significantly improved survival rate. CONCLUSIONS: These data suggest that robust constitutive myocardial A1-AR overexpression induces a dilated cardiomyopathy, whereas delaying A1-AR expression until adulthood ameliorated but did not eliminate the development of cardiac pathology. Thus, the inducible A1-AR transgenic mouse model provides novel insights into the role of adenosine signaling in heart failure and illustrates the potentially deleterious consequences of selective versus nonselective activation of adenosine-signaling pathways in the heart.

Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function. Publishing Authors By Initials

H Funakoshi,TO Chan,JC Good,JR Libonati,J Piuhola,X Chen,SM MacDonnell,LL Lee,DE Herrmann,J Zhang,J Martini,TM Palmer,A Sanbe,J Robbins,SR Houser,WJ Koch,AM Feldman,

For similar natural sciences: time: time factors research abstracts see: natural sciences: time: time factors research

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Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Circulation

VOLUME: 114

Page Numbers: 2240-50

Journal Abbreviation: Circulation

ISSN: 1524-4539

DAY: 6

MONTH: 11

YEAR: 2006

Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 147763

Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function. Keywords Mesh Terms:

KEYWORDS: Time Factors

MESH TERMS: metabolism

Chemical & Substance for Abstract: Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function. Information

Substance Name: Proto-Oncogene Proteins c-akt

Registry Number: EC 2.7.1.37

Grant and Affiliation Information for Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function.

AFFILIATION: Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, PA 19107, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: HL61690

ACRONYM: HL

MEDLINETA: Circulation

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