Abstract 724: Critical Role of Non-Cardiomyocyte Cells in Cardiac Hypertrophy: Selective Ablation of Serotonin 5-HT2B Receptors in Non-Cardiomyocyte Cells Abolishes Isoproterenol-Induced Cardiac Hypertrophy
It is now well established that chronic treatment with beta-adrenergic receptor agonist (e.g., isoproterenol, ISO) leads to cardiac hypertrophy in vivo. However, whether ISO acts on cardiomyocytes, non-cardiomyocytes, or both cell types is currently under debate. Recently, we demonstrated that ablation of the serotonin 5-HT2B receptor (5-HT2BR) in mice prevents the cardiac hypertrophy induced by chronic ISO exposure. In light of this finding, we sought to identify the ISO-responsive cells by crossing 5-HT2BR knock-out mice with mice expressing 5-HT2BRs only in cardiomyocytes (via the myosin heavy chain promoter). We perfused these mice (MHC-5-HT2B/+, 5-HT2B−/−) with ISO (30 μg/g/d) for 7 days and measured cardiac parameters by echocardiography. We found that chronic ISO infusion lead to a significant increase in left ventricular mass:body weight ratio in the MHC-5-HT2B/+, 5-HT2B+/+ mice (6.1 ± 0.4 on day 7 vs 4.6 ± 0.2 on day 0, n = 7) and in the MHC-5-HT2B/+, 5-HT2B+/− mice (7.1 ± 0.4 on day 7 vs 3.8 ± 0.4 on day 0, n = 5). Notably, we observed no hypertrophic ISO response in the MHC-5-HT2B/+, 5-HT2B−/− mice(4.4 ± 0.3 on day 7 vs 4.2 ± 0.2 on day 0, n = 7), in accord with the results obtained using global 5-HT2B−/− mice(4.0 ± 0.5 on day 7 vs 3.8 ± 0.5 on day 0, n = 4). To confirm our findings, we are generating temporo-spatial 5-HT2BRs knock-out mice by crossing 5-HT2BR floxed mice with α-MHC tamoxifen-inducible Cre recombinase mice. Towards a more detailed view of the cellular mechanisms underlying beta-adrenergic receptor agonist-induced hypertrophy, we have previously shown that ISO-stimulated hypertrophic cytokine release is abolished in 5-HT2BR −/− cardiac fibroblasts. We conclude that 5-HT2BR expression in non-cardiomyocyte cells is necessary for ISO-induced cardiac hypertrophy. Importantly, these results provide evidence that cardiac hypertrophy develops not by direct stimulation of cardiac beta-adrenergic receptors but rather by a mechanism involving 5-HT2BR-expressing non-cardiomyocytes.