Key result
The cardiac ventricular 5-HT4 receptor mRNA expression and inotropic responsiveness are highest in late foetal development, decrease to adult levels, and are reactivated in heart failure.
Why the study?
Does the 5-HT4 receptor represent a fetal cardiac gene program that is reactivated in heart failure?
Does the 5-HT4 receptor represent a fetal cardiac gene program that is reactivated in heart failure?
The 5-HT4 receptor is functional in late fetal cardiac development and is reactivated in adult heart failure, suggesting it is part of a fetal cardiac gene program.
5-HT4 reactivation in HF may reflect fetal gene program; hypothesis-generating, needs human validation before clinical consideration.
A positive inotropic responsiveness to serotonin, mediated by 5-HT(4) and 5-HT(2A) receptors, appears in the ventricle of rats with post-infarction congestive heart failure (HF) and pressure overload-induced hypertrophy. A hallmark of HF is a transition towards a foetal genotype which correlates with loss of cardiac functions. Thus, we wanted to investigate whether the foetal and neonatal cardiac ventricle displays serotonin responsiveness. Wistar rat hearts were collected day 3 and 1 before expected birth (days -3 and -1), as well as day 1, 3, 5 and 113 (age matched with Sham and HF) after birth. Hearts from post-infarction HF and sham-operated animals (Sham) were also collected. Heart tissue was examined for mRNA expression of 5-HT(4), 5-HT(2A) and 5-HT(2B) serotonin receptors, 5-HT transporter, atrial natriuretic peptide (ANP) and myosin heavy chain (MHC)-α and MHC-β (real-time quantitative RT-PCR) as well as 5-HT-receptor-mediated increase in contractile function exvivo (electrical field stimulation of ventricular strips from foetal and neonatal rats and left ventricular papillary muscle from adult rats in organ bath). Both 5-HT(4) mRNA expression and functional responses were highest at day -3 and decreased gradually to day 5, with a further decrease to adult levels. In HF, receptor mRNA levels and functional responses reappeared, but to lower levels than in the foetal ventricle. The 5-HT(2A) and 5-HT(2B) receptor mRNA levels increased to a maximum immediately after birth, but of these, only the 5-HT(2A) receptor mediated a positive inotropic response. We suggest that the 5-HT(4) receptor is a representative of a foetal cardiac gene program, functional in late foetal development and reactivated in heart failure.
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Brattelid et al. (2012) studied Heart Failure. Serotonin (5-HT) vs. Sham-operated and normal adult rats was evaluated on 5-HT4 receptor mRNA expression and 5-HT4-mediated inotropic response. The cardiac ventricular 5-HT4 receptor mRNA expression and inotropic responsiveness are highest in late foetal development, decrease to adult levels, and are reactivated in heart failure.
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