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Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation.
Gao, Mei Hua; Lai, N Chin; Giamouridis, Dimosthenis; Kim, Young Chul; Tan, Zhen; Guo, Tracy; Dillmann, Wolfgang H; Suarez, Jorge; Hammond, H Kirk.
Afiliación
  • Gao MH; VA San Diego Healthcare System and Department of Medicine, University of California San Diego.
  • Lai NC; VA San Diego Healthcare System and Department of Medicine, University of California San Diego.
  • Giamouridis D; VA San Diego Healthcare System and Department of Medicine, University of California San Diego.
  • Kim YC; VA San Diego Healthcare System and Department of Medicine, University of California San Diego.
  • Tan Z; VA San Diego Healthcare System and Department of Medicine, University of California San Diego.
  • Guo T; VA San Diego Healthcare System and Department of Medicine, University of California San Diego.
  • Dillmann WH; VA San Diego Healthcare System and Department of Medicine, University of California San Diego.
  • Suarez J; VA San Diego Healthcare System and Department of Medicine, University of California San Diego.
  • Hammond HK; VA San Diego Healthcare System and Department of Medicine, University of California San Diego.
JACC Basic Transl Sci ; 1(7): 617-629, 2016 Dec.
Article en En | MEDLINE | ID: mdl-28670631
OBJECTIVE: To test the hypothesis that cardiac-directed expression of the cytoplasmic domains of adenylyl cyclase-6 (AC6) would have beneficial effects on the heart. BACKGROUND: Eliminating the two transmembrane domains of AC6 yields a protein with an intact catalytic domain that is disengaged from membrane-associated ß-adrenergic receptor stimulation, but with enhanced propensity for intracellular interactions. METHODS: We constructed a peptide of the C1 and C2 segments of AC6 (C1C2), expressed C1C2 in an adenovirus vector and generated transgenic lines with cardiac-directed C1C2 expression, which underwent sustained isoproterenol (Iso) infusion. RESULTS: Gene transfer of C1C2 in cardiac myocytes showed reduced cAMP generation in response to Iso-stimulation. C1C2 transgenic mice had normal left ventricular (LV) structure and function. LV samples from C1C2 mice showed diminished Iso-stimulated cAMP generation but normal LV contractile responses, suggesting a compensatory mechanism. Cardiac myocytes from C1C2 mice showed increased Iso-stimulated Ca2+ release and reduced time to peak Ca2+ release. After 7 days Iso infusion, control mice tended to show reduced LV function, but C1C2 mice showed increases in both LV peak +dP/dt and peak -dP/dt indicating enhanced LV systolic and diastolic function. LV from C1C2 mice showed a 2.6-fold increase in SERCA2a protein, and cardiac myocytes showed increased Ca2+ release, reduced time to peak Ca2+ release and reduced Tau. CONCLUSIONS: In C1C2 mice, sustained isoproterenol infusion increases rather than decreases LV function. Reduced cAMP generation and resistance to catecholamine cardiomyopathy are attractive features of this novel AC-related protein.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: JACC Basic Transl Sci Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: JACC Basic Transl Sci Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos