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Gao MH, Lai NC, Giamouridis D, et al. Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation. JACC Basic Transl Sci. 2016;1(7):617-629doi: 10.1016/j.jacbts.2016.08.004.
Gao, M. H., Lai, N. C., Giamouridis, D., Kim, Y. C., Tan, Z., Guo, T., Dillmann, W. H., Suarez, J., & Hammond, H. K. (2016). Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation. JACC. Basic to translational science, 1(7), 617-629. https://doi.org/10.1016/j.jacbts.2016.08.004
Gao, Mei Hua, et al. "Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation." JACC. Basic to translational science vol. 1,7 (2016): 617-629. doi: https://doi.org/10.1016/j.jacbts.2016.08.004
Gao MH, Lai NC, Giamouridis D, Kim YC, Tan Z, Guo T, Dillmann WH, Suarez J, Hammond HK. Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation. JACC Basic Transl Sci. 2016 Dec;1(7):617-629. doi: 10.1016/j.jacbts.2016.08.004. PMID: 28670631; PMCID: PMC5490496.
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JACC Basic Transl Sci. 2016 Dec;1(7):617-629. doi: 10.1016/j.jacbts.2016.08.004.

Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation.

JACC. Basic to translational science

Mei Hua Gao, N Chin Lai, Dimosthenis Giamouridis, Young Chul Kim, Zhen Tan, Tracy Guo, Wolfgang H Dillmann, Jorge Suarez, H Kirk Hammond

Affiliations

  1. VA San Diego Healthcare System and Department of Medicine, University of California San Diego.

PMID: 28670631 PMCID: PMC5490496 DOI: 10.1016/j.jacbts.2016.08.004

Abstract

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 β-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.

Keywords: cardiomyopathy; catecholamine; gene therapy; heart failure

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