Abstract 3600: Endothelin-1 Exaggerates Cardiomyocyte Hypertrophy Through a Presynaptic and Norepinephrine-dependent Mechanism
Background: Endothelin-1 (ET-1) induces cardiomyocyte (CM) hypertrophy by activating endothelin A receptors (ET-A) on CMs. We have shown that ET-1 enhances norepinephrine (NE) release from sympathetic nerve endings by inhibiting NE re-uptake. Whether the latter mechanism contributes to the hypertrophic effects of ET-1 is still unclear.
Methods: To characterize the interaction between sympathetic neurons (SNs) and CMs we established a CM-SN-coculture. CM-monocultures vs. CM-SN-cocultures were treated with ET-1, the ET-A antagonist darusentan and adrenergic receptor antagonists (ARA). Adenoviral overexpression of histone deacetylase 5 (HDAC5) enabled us to assess HDAC5 nuclear export as an indicator of hypertrophic signaling. As an additional readout, we measured protein kinase D (PKD) activation, an inductor of nuclear HDAC5 export. Cardiac NE re-uptake was measured in Langendorff-perfused rat hearts.
Results: In CM-SN-coculture, ET-1 led to a significant increased hypertrophic response as compared to CM-monoculture (CM area: 4273±383.5 μm2 vs. 2650±164.7 μm2, n>19, p<0.05). Importantly, this effect was not only inhibited by darusentan but also by ARA. Nuclear export of HDAC5 was significant increased after stimulation with ET-1 (10nM, 24h) (n>40, cytosol/nucleus-intensity 0.51±0.2 vs. 0.43±0.12 p<0.01). In vivo, darusentan normalized NE-re-uptake in salt-sensitive Dahl rats, which was associated with enhanced NE tissue levels in the left ventricle and reduced NE plasma levels as well as reduced myocardial hypertrophy and a significant improved cardiac function.
Conclusion: ET-1 induces cardiomyocyte hypertrophy not only by direct activation of ET-A on CMs but also by enhancing NE net release from sympathetic nerve endings, which signals towards PKD and HDAC5. These findings explain why clinical heart failure trials with ET-A antagonists on top of beta blocker treatment might have failed to show an improved outcome. Hence, ET-A antagonists could be an option for patients with heart failure and beta-blocker intolerance.