Cardiac-directed adenylyl cyclase expression improves heart function in murine cardiomyopathy.
BACKGROUND
We tested the hypothesis that increased cardiac myocyte adenylyl cyclase (AC) content increases cardiac function and response to catecholamines in cardiomyopathy.


RESULTS
Transgenic mice with cardiac-directed expression of AC type VI (ACVI) were crossbred with mice with cardiomyopathy induced by cardiac-directed Gq expression. Gq mice had dilated left ventricles, reduced heart function, decreased cardiac responsiveness to catecholamine stimulation, and impaired beta-adrenergic receptor (betaAR)-dependent and AC-dependent cAMP production. Gq/AC mice showed improved basal cardiac function in vivo (P=0.01) and ex vivo (P<0.0005). When stimulated through the betaAR, cardiac responsiveness was increased (P=0.02), and cardiac myocytes showed increased cAMP production in response to isoproterenol (P=0.03) and forskolin (P<0.0001).


CONCLUSIONS
Increasing myocardial ACVI content in cardiomyopathy restores cAMP-generating capacity and improves cardiac function and responsiveness to betaAR stimulation.
Roth
D M
DM
Department of Medicine, VAMC-San Diego and University of California, San Diego, CA, USA.
Gao
M H
MH
Lai
N C
NC
Drumm
J
J
Dalton
N
N
Zhou
J Y
JY
Zhu
J
J
Entrikin
D
D
Hammond
H K
HK
D000262:Adenylyl Cyclases / Q000235:genetics*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000628:therapy*; D000242:Cyclic AMP / Q000096:biosynthesis; D004452:Echocardiography; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015316:Genetic Therapy; D006334:Heart Function Tests; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D019076:Transgenes / Q000502:physiology
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol