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

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 4 week 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 4 weeks 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.

• Authors: Yasuo Sugano, N Chin Lai, Mei Hua Gao, Amy L Firth, Jason X-J Yuan, Wilbur Y W Lew, H Kirk Hammond
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 405 Issue 3 Pg. 349-55 (Feb 18 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 21195051 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011. Published by Elsevier Inc.

Chemical References

• Calcium-Binding Proteins
• NCX1 protein, mouse
• Receptors, Neuropeptide Y
• Sodium-Calcium Exchanger
• phospholamban
• Caffeine
• neuropeptide Y4 receptor
• Adenylyl Cyclases
• adenylyl cyclase 6
• Calcium

Topics

• Adenylyl Cyclases (biosynthesis, genetics)
• Animals
• Caffeine (pharmacology)
• Calcium (metabolism)
• Calcium-Binding Proteins (metabolism)
• Dilatation, Pathologic (enzymology, physiopathology)
• Enzyme Activation
• Hypertrophy, Left Ventricular (enzymology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Phosphorylation
• Pressure
• Receptors, Neuropeptide Y (metabolism)
• Sodium-Calcium Exchanger (metabolism)
• Ventricular Dysfunction, Left (enzymology, physiopathology)