Serotonin 5-HT(2B) receptor blockade prevents reactive oxygen species-induced cardiac hypertrophy in mice.

Abstract

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.

• Authors: Laurent Monassier, Marc-André Laplante, Fabrice Jaffré, Pascal Bousquet, Luc Maroteaux, Jacques de Champlain
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 52 Issue 2 Pg. 301-7 (Aug 2008) ISSN: 1524-4563 [Electronic] United States
• PMID: 18591460 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Indoles
• Quinolines
• Reactive Oxygen Species
• Receptor, Serotonin, 5-HT2B
• SB 215505
• Serotonin Antagonists
• Superoxides
• Angiotensin II
• NADP
• Isoproterenol

Topics

• Angiotensin II (pharmacology)
• Animals
• Cardiomegaly (diagnostic imaging, prevention & control)
• Disease Models, Animal
• Echocardiography, Doppler
• Indoles (pharmacology)
• Isoproterenol (pharmacology)
• Mice
• Mice, Inbred Strains
• NADP (metabolism)
• Probability
• Quinolines (pharmacology)
• Random Allocation
• Reactive Oxygen Species (pharmacology)
• Receptor, Serotonin, 5-HT2B (drug effects, metabolism)
• Reference Values
• Sensitivity and Specificity
• Serotonin Antagonists (pharmacology)
• Superoxides (analysis)