Serotonin 5-HT2B receptor blockade prevents reactive oxygen species-induced cardiac hypertrophy in mice

We established previously that 5-HT2B 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-HT2B receptors could be involved in the development of cardiac hypertrophy associated with superoxide anion production. Therefore, we measured the effects of serotonergic 5-HT2B 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- HT2B 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-HT2B 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-HT2B 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.