Serotonin 5-HT(2B) receptor blockade prevents reactive oxygen species-induced cardiac hypertrophy in mice.
We established previously that 5-HT(2B) receptors are involved in cardiac hypertrophy through the regulation of hypertrophic cytokines in cardiac fibroblasts. Moreover, the generation of reactive oxygen species and tumor necrosis factor-alpha through the activation of reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase has been implicated in cardiac hypertrophy. In this study, we investigated whether 5-HT(2B) receptors could be involved in the development of cardiac hypertrophy associated with superoxide anion production. Therefore, we measured the effects of serotonergic 5-HT(2B) receptor blockade on left-ventricular superoxide anion generation in 2 established pharmacological models of cardiac hypertrophy, ie, angiotensin II and isoproterenol infusions in mice. Angiotensin II infusion for 14 days increased superoxide anion concentration (+32%), NAD(P)H oxidase maximal activity (+84%), and p47(phox) NAD(P)H oxidase subunit expression in the left ventricle together with hypertension (+37 mm Hg) and cardiac hypertrophy (+17% for heart weight:body weight). The 5-HT(2B) receptor blockade by a selective antagonist (SB215505) prevented the increase in cardiac superoxide generation and hypertrophy. Similarly, infusion for 5 days of isoproterenol increased left-ventricular NAD(P)H oxidase activity (+48%) and cardiac hypertrophy (+31%) that were prevented by the 5-HT(2B) receptor blockade. Finally, in the primary culture of left-ventricular cardiac fibroblasts, angiotensin II and isoproterenol stimulated NAD(P)H oxidase activity. This activation was prevented by SB215505. These findings suggest that the 5-HT(2B) receptor may represent a new target to reduce cardiac hypertrophy and oxidative stress. Its blockade affects both angiotensin II and beta-adrenergic trophic responses without significant hemodynamic alteration.
Monassier
Laurent
L
INSERM U-715, Faculté de Médecine, 11 rue Humann, Strasbourg, France. laurent.monassier@medecine.u-strasbg.fr
Laplante
Marc-André
MA
Jaffré
Fabrice
F
Bousquet
Pascal
P
Maroteaux
Luc
L
de Champlain
Jacques
J
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000517:prevention & control*; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D007211:Indoles / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009249:NADP / Q000378:metabolism; D011336:Probability; D011804:Quinolines / Q000494:pharmacology*; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000494:pharmacology; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects* / Q000378:metabolism; D012016:Reference Values; D012680:Sensitivity and Specificity; D012702:Serotonin Antagonists / Q000494:pharmacology; D013481:Superoxides / Q000032:analysis*
D007211:Indoles; D011804:Quinolines; D017382:Reactive Oxygen Species; D044403:Receptor, Serotonin, 5-HT2B; C118948:SB 215505; D012702:Serotonin Antagonists; D013481:Superoxides; D000804:Angiotensin II; D009249:NADP; D007545:Isoproterenol