Tonic beta-adrenergic drive provokes proinflammatory and proapoptotic changes in aging mouse heart.
Tonic activation of adrenergic drive has been found to be associated with aging, and its further activation is also seen in aging patients with major surgery or congestive heart failure. Nevertheless, its potential effect on the aging heart remains enigmatic. In the present study, at baseline, significant inflammatory and apoptotic changes were found in the aging mouse (20 months old), as evidenced by increases in inducible nitric oxide synthase (iNOS) expression, myocardial apoptosis in the heart, and C-reactive protein (CRP) release in the circulation. These phenotypic changes in aging animals can be induced in young animals (3 months old) by chronic beta-adrenergic receptor (AR) stimulation with isoproterenol (ISO), and they can be markedly reduced in aging animals by chronic beta-blockade with propranolol. Compared with young animals, chronic beta-AR stimulation with ISO in aging animals induced larger increases in iNOS expression, nitrotyrosine formation in the heart, and nitric oxide (NO) production and CRP release in the circulation; it also accelerated myocardial apoptosis and resulted in an enlarged infarct size when animals were subjected to myocardial ischemia and reperfusion (MI/R). However, the pretreatment of 1400W (N-(3-(aminomethyl) benzyl)acetamidine)-a specific iNOS inhibitor-significantly reduced iNOS-mediated nitrative stress associated with a marked decrease in myocardial apoptosis and infarct size in aging mice. These results demonstrate that tonic activation of the beta-adrenergic system associated with aging induces proinflammatory and proapoptotic changes in the heart and that additional beta-AR stimulation results in an exaggerated nitrative stress, mediated by iNOS, that is associated with more severe myocardial injury in aging mice.
Hu
Aihua
A
Department of Anesthesiology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Jiao
Xiangying
X
Gao
Erhe
E
Li
Yonghai
Y
Sharifi-Azad
Said
S
Grunwald
Zvi
Z
Ma
Xin L
XL
Sun
Jian-Zhong
JZ
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000375:Aging / Q000187:drug effects*; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001596:Benzylamines / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D007249:Inflammation / Q000139:chemically induced*; D018836:Inflammation Mediators / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000139:chemically induced; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000578:Amidines; D001596:Benzylamines; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009573:Nitrites; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D007545:Isoproterenol