Adenylyl cyclase increases survival in cardiomyopathy.
BACKGROUND
To test the hypothesis that increased cardiac adenylyl cyclase type VI (AC(VI)) content, which results in increased cAMP generation, would increase survival in cardiomyopathy, we crossbred mice with Gq-associated cardiomyopathy and those with cardiac-directed expression of AC(VI). We also assessed myocardial hypertrophy after prolonged cardiac expression of Gq versus coexpression of Gq and AC(VI).


RESULTS
Three experimental groups, Gq/AC (double positive), Gq, and control (double negative), were studied. Survival was increased by cardiac-directed expression of AC(VI) (P<0.0001), and Gq/AC mice had survival rates indistinguishable from control mice. Myocardial hypertrophy developed in older Gq mice but was abrogated by cardiac expression of AC(VI), as documented by the ratio of ventricular weight to tibial length (Gq, 11.93+/-0.99 mg/mm, n=11; Gq/AC, 8.00+/-0.73 mg/mm, n=9; P<0.01) and by left ventricular cardiac myocyte size (Gq, 2800+/-254 microm2, n=4; Gq/AC, 1721+/-166 microm2, n=5; P<0.01). Hearts of Gq mice were dilated, and function was impaired. Concurrent expression of AC reduced end-diastolic diameter (Gq, 4.20+/-0.15 mm, n=12; Gq/AC, 3.68+/-0.12 mm, n=7; P<0.05) and increased fractional shortening (Gq, 32+/-1%, n=12; Gq/AC, 41+/-2%, n=7; P<0.001). Cardiac myocytes from Gq/AC mice showed increased forskolin-stimulated cAMP production (Gq, 3.8+/-1.3 fmol/cell, n=5; Gq/AC, 10.7+/-2.6 fmol/cell, n=6; P<0.02), documenting increased AC function.


CONCLUSIONS
Cardiac-directed expression of AC(VI) restores myocyte AC function, improves heart function, increases cAMP generation, abrogates myocardial hypertrophy, and increases survival in Gq cardiomyopathy.
Roth
David M
DM
VA San Diego Healthcare System, San Diego, CA 92161, USA.
Bayat
Hamed
H
Drumm
Jeffrey D
JD
Gao
Mei Hua
MH
Swaney
James S
JS
Ander
Aziz
A
Hammond
H Kirk
HK
D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D015996:Survival Rate; D014463:Ultrasonography
D000242:Cyclic AMP; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6