Activated expression of cardiac adenylyl cyclase 6 reduces dilation and dysfunction of the pressure-overloaded heart

Yasuo Sugano, N. Chin Lai, Mei Hua Gao, Amy L. Firth, Jason X.J. Yuan, Wilbur Y.W. Lew, H. Kirk Hammond

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Background and objective: Cardiac-directed adenylyl cyclase 6 (AC6) expression attenuates left ventricular (LV) hypertrophy and dysfunction in cardiomyopathy, but its effects in the pressure-overloaded heart are unknown. Methods: Mice with cardiac-directed and regulated expression of AC6 underwent transaortic constriction (TAC) to induce LV pressure overload. Ten days prior to TAC, and for the duration of the 4week study, cardiac myocyte AC6 expression was activated in one group (AC-On) but not the other (AC-Off). Multiple measures of LV systolic and diastolic function were obtained 4week after TAC, and LV samples assessed for alterations in Ca2+ signaling. Results: LV contractility, as reflected in the end-systolic pressure-volume relationship (Emax), was increased (p=0.01) by activation of AC6 expression. In addition, diastolic function was improved (p<0.05) and LV dilation was reduced (p<0.05). LV samples from AC-On mice showed reduced protein expression of sodium/calcium exchanger (NCX1) (p<0.05), protein phosphatase 1 (PP1) (p<0.01), and increased phosphorylation of phospholamban (PLN) at Ser16 (p<0.05). Finally, sarcoplasmic reticulum (SR) Ca2+ content was increased in cardiac myocytes isolated from AC-On mice (p<0.05). Conclusions: Activation of cardiac AC6 expression improves function of the pressure-overloaded and failing heart. The predominant mechanism for this favorable adaptation is improved Ca2+ handling, a consequence of increased PLN phosphorylation, reduced NCX1, reduced PP1 expression, and increased SR Ca2+ content.

Original languageEnglish (US)
Pages (from-to)349-355
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume405
Issue number3
DOIs
StatePublished - Feb 18 2011

Keywords

  • Animal models of human disease
  • Heart failure
  • Hypertrophy
  • Myocardial contraction
  • Remodeling

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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