Table 1.

AC6 expression and cardiac function

Model	Findings	Ref
Transgenic mice
AC6	No change in basal cAMP production and LV function; increased LV function in response to βAR stimulation	39
AC6	Facilitation of atrioventricular nodal conduction without altering sinus node function	68
AC6 and acute MI	Reduced mortality in acute MI; improved SR Ca2+ uptake; normalized PLB phosphorylation	50
AC6 and MI	Decreased fibrosis and increased engraftment of iPS cells in the infarcted area	51
AC6 × Gαq	Restored cAMP generation capacity; increased LV function and βAR responsiveness	44
AC6 × Gαq	Decreased LV hypertrophy, increased LV function and prolonged survival in Gαq cardiomyopathy	45
AC6 × Gαq	Normalized LV SR Ca2+ uptake and PLB phosphorylation in Gαq cardiomyopathy	48
AC6 × Gαq	No alteration in heart rate regulation	47
AC6 × Gαq	Corrects prolonged action potential duration in Gαq cardiomyopathy	49
AC6-tet	Increased LV responsiveness to βAR stimulation after activation of cardiac-directed AC6 expression	40
AC6-tet in CHF	Increased LV function of failing heart (CHF induced by MI); normalized cTnI phosphorylation	3
AC6-tet and aging	Improved Ca2+ handling and increased LV function in mice aged 24 months, but not in young mice	57
AC6 deletion	Marked adverse effects on Ca2+ uptake; reduced LV function in response to βAR stimulation	37
Gene transfer in cells
NRCM	AC6 amount determines NRCM response to βAR stimulation	38
NRCM	AC6 reduces PLB expression by increasing ATF3 content through cAMP-independent pathway	58
NRCM	AC6 increases PLB phosphorylation by activating Akt (cAMP independent)	60
NRCM	AC6 regulates Akt activity in NRCM (cAMP independent)	59
NRCM	AC6 vs β1AR: differences in intracellular distribution—an important determinant of biological effects	69
ARCM	AC6 and AC6mut (catalytically inactive) have similar benefits in ARCM	70
In vivo gene transfer
C57BL/6 mouse	Indirect intracoronary delivery of Ad.AC6: increased LV function in response to βAR stimulation	31
Gαq mouse	Intracoronary delivery of Ad.AC6: increased LV function in Gαq cardiomyopathy	46
Normal pig	Intracoronary delivery of Ad.AC6: increased LV function in response to βAR stimulation	41
CHF pig	Intracoronary delivery of Ad.AC6: increased function of failing LV	42
Normal pig	Intracoronary delivery of Ad.AC6: persisted cardiac AC6 expression for 10 weeks without toxicity	—a

Abbreviations: AC6, adenylyl cyclase 6; ARCM, adult rat cardiac myocytes; ATF3, activating transcription factor 3; βAR, β-adrenergic receptor; cAMP, 3′,5′-cyclic adenine monophosphate; CHF, congestive heart failure; cTnI, cardiac troponin I; iPS cells, induced pluripotent stem cells; LV, left ventricular; MI, myocardial infarction; NRCM, neonatal rat cardiac myocytes; PLB, phospholamban; SR, sarcoplasmic reticulum.

^aFood and Drug Administration (FDA) Investigational New Drug (IND) application.