Increased cardiac adenylyl cyclase expression is associated with increased survival after myocardial infarction.
BACKGROUND
Cardiac-directed expression of adenylyl cyclase type VI (AC(VI)) in mice results in structurally normal hearts with normal basal heart rate and function but increased responses to catecholamine stimulation. We tested the hypothesis that increased left ventricular (LV) AC(VI) content would increase mortality after acute myocardial infarction (MI).


RESULTS
Transgenic mice with cardiac-directed AC(VI) expression and their transgene-negative littermates (control) underwent coronary ligation, and survival, infarct size, and LV size and function were assessed 1 to 7 days after MI. Mice with increased AC(VI) expression had increased survival (control 41%, AC(VI) 74%; P = 0.004). Infarct size and myocardial apoptotic rates were similar in AC(VI) and control mice; however, AC(VI) mice had less LV dilation (P < 0.001) and increased ejection fractions (P < 0.03). Three days after MI, studies in isolated perfused hearts showed that basal LV +dP/dt was similar, but graded dobutamine infusion was associated with a more robust LV contractile response in AC(VI) mice (P < 0.05). Increased LV function was associated with increases in cAMP generation (P = 0.0002), phospholamban phosphorylation (P < 0.04), sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) affinity for calcium (P < 0.015), and reduced AV block (P = 0.04).


CONCLUSIONS
In acute MI, increased cardiac AC(VI) content attenuates adverse LV remodeling, preserves LV contractile function, and reduces mortality.
Takahashi
Toshiyuki
T
Department of Medicine, University of California, San Diego, Calif., USA.
Tang
Tong
T
Lai
N Chin
NC
Roth
David M
DM
Rebolledo
Brian
B
Saito
Miho
M
Lew
Wilbur Y W
WY
Clopton
Paul
P
Hammond
H Kirk
HK
D000262:Adenylyl Cyclases / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000032:analysis / Q000502:physiology; D005260:Female; D019204:GTP-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006352:Heart Ventricles / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology*; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015996:Survival Rate; D020257:Ventricular Remodeling / Q000502:physiology
D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D002118:Calcium