Activation of adenosine A1 receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model.
Sympathomimetic stimulation, angiotensin II, or endothelin-1 is considered to be an essential stimulus mediating ventricular hypertrophy. Adenosine is known to protect the heart from excessive catecholamine exposure, reduce production of endothelin-1, and attenuate the activation of the renin-angiotensin system. These findings suggest that adenosine may also attenuate myocardial hypertrophy. To verify this hypothesis, we examined whether activation of adenosine receptors can attenuate cardiac hypertrophy and reduce the risk of heart failure. Our in vitro study of neonatal rat cardiomyocytes showed that 2-chloroadenosine (CADO), a stable adenosine analogue, inhibits protein synthesis of cardiomyocytes induced by phenylephrine, endothelin-1, angiotensin II, or isoproterenol, which were mimicked by the stimulation of adenosine A1 receptors. For our in vivo study, cardiac hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6 male mice. Four weeks after TAC, both heart to body weight ratio (6.80+/-0.18 versus 8.34+/-0.33 mg/g, P<0.0001) as well as lung to body weight ratio (6.23+/-0.27 versus 10.03+/-0.85 mg/g, P<0.0001) became significantly lower in CADO-treated mice than in the TAC group. Left ventricular fractional shortening and left ventricular dP/dtmax were improved significantly by CADO treatment. Similar results were obtained using the selective adenosine A1 agonist N6-cyclopentyladenosine (CPA). A nonselective adenosine antagonist, 8-(p-sulfophenyl)-theophylline, and a selective adenosine A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine, eliminated the antihypertrophic effect of CADO and CPA, respectively. The plasma norepinephrine level was decreased and myocardial expression of regulator of G protein signaling 4 was upregulated in CADO-treated mice. These results indicate that the stimulation of adenosine receptors attenuates both the cardiac hypertrophy and myocardial dysfunction via adenosine A1 receptor-mediated mechanisms.
Liao
Yulin
Y
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.
Takashima
Seiji
S
Asano
Yoshihiro
Y
Asakura
Masanori
M
Ogai
Akiko
A
Shintani
Yasunori
Y
Minamino
Tetsuo
T
Asanuma
Hiroshi
H
Sanada
Shoji
S
Kim
Jiyoong
J
Ogita
Hisakazu
H
Tomoike
Hitonobu
H
Hori
Masatsugu
M
Kitakaze
Masafumi
M
D015762:2-Chloroadenosine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000601:surgery; D002478:Cells, Cultured; D003250:Constriction; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011956:Receptors, Cell Surface / Q000819:agonists; D017725:Ventricular Pressure
D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011956:Receptors, Cell Surface; D015762:2-Chloroadenosine; D017868:Cyclic AMP-Dependent Protein Kinases; D020962:Heterotrimeric GTP-Binding Proteins