Bitransgenesis with beta(2)-adrenergic receptors or adenylyl cyclase fails to improve beta(1)-adrenergic receptor cardiomyopathy.
Cardiomyopathic effects of beta-adrenergic receptor (betaAR) signaling are primarily due to the beta(1)AR subtype. beta(1)/beta(2)AR and beta(1)/adenylyl cyclase type 5 (AC5) bitransgenic mice were created to test the hypothesis that beta(2)AR or AC5 co-overexpression has beneficial effects in beta(1)AR-mediated cardiomyopathy. In young mice, beta(1)/beta(2) hearts had a greater increase in basal and isoproterenol-stimulated contractility compared to beta(1)/AC5 and beta(1)AR hearts. By 6 months, beta(1)AR and beta(1)/beta(2) hearts retained elevated basal contractility but were unresponsive to agonist. In contrast, beta(1)/AC5 hearts maintained a small degree of agonist responsiveness, which may be due to a lack of beta(1)AR downregulation that was noted in beta(1)- and beta(1)/beta(2) hearts. However, by 9 -months, beta(1), beta(1)/beta(2), and beta(1)/AC5 mice had all developed severely depressed fractional shortening in vivo and little response to agonist. p38 mitogen activated protein kinase (MAPK) was minimally activated by beta(1)AR, but was markedly enhanced in the bitransgenics. Akt activation was only found with the bitransgenics. The small increase in cystosolic second mitochondria-derived activator of caspase (Smac), indicative of apoptosis in 9-month beta(1)AR hearts, was suppressed in beta(1)/AC5, but not in beta(1)/beta(2), hearts. Taken together, the unique signaling effects of enhanced beta(2)AR and AC5, which have the potential to afford benefit in heart failure, failed to salvage ventricular function in beta(1)AR-mediated cardiomyopathy.
Petrashevskaya
Natalia
N
Cardiopulmonary Genomics Program, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Gaume
Brigitte R
BR
Mihlbachler
Kathryn A
KA
Dorn
Gerald W
GW
Liggett
Stephen B
SB
D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D009202:Cardiomyopathies / Q000209:etiology*; D002352:Carrier Proteins / Q000502:physiology; D004452:Echocardiography; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D024101:Mitochondrial Proteins; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D000262:Adenylyl Cyclases