Abstract 338: Isoproterenol-induced Cardiac Hypertrophy Is Mediated By Angiotensin II And Is Prevented By Selective Ablation Of The Serotonin 5-ht2b receptor In Non-cardiomyocytes Cells
We previously demonstrated that pharmacological inhibition or genetic ablation of the 5-HT2B receptor (5-HT2BR) in global knockout mice abolished beta-adrenergic agonist (isoproterenol, ISO) but also angiotensin II (AngII)-induced cardiac hypertrophy (CH) in vivo. We suggested that cardiac fibroblasts (CFs) could be critically involved in this CH process because ISO-induced hypertrophic cytokine release (IL-6, TNF-alpha, IL-1 beta and TGF-beta1) is abolished in KO 5-HT2BR adult CFs. However, because cardiomyocytes (CMs) also expressed 5-HT2BR, cellular type expressing 5-HT2BR involved in this process in vivo is unknown. First of all, we generated new transgenic mice with a 5-HT2BR expression restricted to CMs by crossing global KO mice and mice with a 5-HT2BR overexpression in CMs. We showed that these mice with genetic ablation of serotonin 5-HT2BR exclusively in non-CM cells abolishes ISO (30 μg/g/d, 7 days)-induced left ventricular mass:body weight ratio increase (4.4 ± 0.3 on day 7 vs 4.2 ± 0.2 on day 0, n = 7) compared to mice with a global 5-HT2BR expression (6.1 ± 0.4 on d7 vs 4.6 ± 0.2 on d0, p < 0.001, n = 7). This inhibition is also associated to an inhibition of hypertrophic cytokine plasma levels increase. Because it was previously demonstrated that beta-adrenergic receptor stimulation leads to AngII release in heart by CFs, we infused angiotensinogen null mice (Agt−/−) with ISO for 7 days. These mice did not develop CH after ISO infusion (4.3 ± 0.3 on d7 vs 4.5 ± 0.2 on d0, n = 5) compared to the wildtype mice (WT) (6.0 ± 0.4 on d7 vs 4.4 ± 0.1 on d0, p < 0.001, n = 5), demonstrating that ISO-induced CH is completely mediated by AngII. Moreover, ISO (10 μM)-dependent hypertrophic cytokine release was abolished in Agt−/− CFs culture or was prevented by the AT-1R antagonist ZD7155 (100 nM) in WT CFs cultures. In conclusion, we demonstrated that selective ablation of 5-HT2BR in non-CM cells abolishes ISO-induced CH. This ISO-induced CH response is totally mediated by AngII mainly via the AT-1R expressed by non-CM cells. Our results highlight for the first time that 5-HT2BR and AT-1R interact together and demonstrate that 5-HT2BR is critically required in non-CM cells for AngII/AT-1R pathway-induced CH.