Increased myocardial contractility and enhanced exercise function in transgenic mice overexpressing either adenylyl cyclase 5 or 8.
OBJECTIVE
ss-adrenergic receptors (ssARs) are powerful regulators of cardiac function in vivo, activating heterotrimeric G proteins and the effector molecule adenylyl cyclase (AC). Interestingly, cardiac-specific overexpression of different AC isoforms leads to variable changes in cardiac function. Whether AC overexpression affects intrinsic cardiac contractility in an isoform-specific fashion determining a change in exercise capacity is currently unknown.


METHODS
To address this issue, we performed load-independent measurements of cardiac systolic and diastolic function by pressure-volume (PV) loop analysis in intact wild-type mice (WT) and transgenic mice overexpressing the AC isoforms 5 or 8.


RESULTS
Here we show that cardiac overexpression of either AC5 or AC8 transgenic mice determined an increase in intrinsic cardiac contractility. Interestingly, AC8 transgenic mice displayed a significantly greater increase in cardiac contractility and improved active phase of relaxation. Despite these differences detected by PV loop analysis, both AC5 and AC8 mice showed a marked increase in exercise capacity on treadmill testing.


CONCLUSIONS
Our results demonstrate that load-independent measurements of cardiac function are needed to compare different groups of genetically-modified mouse models and to detect subtle AC isoform-specific changes in cardiac performance.
Esposito
Giovanni
G
Division of Cardiology, University Federico II of Naples, Via Pansini 5, 80131 Naples, Italy. espogiov@unina.it
Perrino
Cinzia
C
Ozaki
Tohru
T
Takaoka
Hideyuki
H
Defer
Nicole
N
Petretta
Maria Piera
MP
De Angelis
Maria Carmen
MC
Mao
Lan
L
Hanoune
Jacques
J
Rockman
Howard A
HA
Chiariello
Massimo
M
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D004452:Echocardiography; D017079:Exercise Tolerance / Q000502:physiology*; D005260:Female; D006439:Hemodynamics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015233:Models, Statistical; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology*; D012420:Running / Q000502:physiology
D007527:Isoenzymes; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8; C419510:adenylyl cyclase type V