Open AccessBitransgenesis with β 2 ‐Adrenergic Receptors or Adenylyl Cyclase Fails to Improve β 1 ‐Adrenergic Receptor Cardiomyopathy
Author(s) -
Petrashevskaya Natalia,
Gaume Brigitte R.,
Mihlbachler Kathryn A.,
Dorn II Gerald W.,
Liggett Stephen B.
Publication year - 2008
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/j.1752-8062.2008.00061.x
Subject(s) - adenylyl cyclase , adrenergic receptor , receptor , adrenergic , medicine , endocrinology , cardiomyopathy , alpha 1b adrenergic receptor , alpha 1d adrenergic receptor , beta 3 adrenergic receptor , heart failure
Abstract Cardiomyopathic effects of β‐adrenergic receptor (βAR) signaling are primarily due to the β 1 AR subtype. β 1 /β 2 AR and β 1 /adenylyl cyclase type 5 (AC5) bitransgenic mice were created to test the hypothesis that β 2 AR or AC5 co‐overexpression has beneficial effects in β 1 AR‐mediated cardiomyopathy. In young mice, β 1 /β 2 hearts had a greater increase in basal and isoproterenol‐stimulated contractility compared to β 1 /AC5 and β 1 AR hearts. By 6 months, β 1 AR and β 1 /β 2 hearts retained elevated basal contractility but were unresponsive to agonist. In contrast, β 1 /AC5 hearts maintained a small degree of agonist responsiveness, which may be due to a lack of β 1 AR downregulation that was noted in β 1 ‐ and β 1 /β 2 hearts. However, by 9 ‐months, β 1 , β 1 /β 2 , and β 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 β 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 β 1 AR hearts, was suppressed in β 1 /AC5, but not in β 1 /β 2 , hearts. Taken together, the unique signaling effects of enhanced β 2 AR and AC5, which have the potential to afford benefit in heart failure, failed to salvage ventricular function in β 1 AR‐mediated cardiomyopathy.