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PPARγ and NOTCH Regulate Regional Identity in the Murine Cardiac Outflow Tract

Commented by the ESC WG on Development, Anatomy & Pathology

Basic Science - Cardiac Diseases - Congenital Heart Disease
ESC Working Groups


Outflow tract anomalies form a large part of congenital heart disease, and usually of the more complex and severe kind. Developmental studies established its origin from the second heart field with contribution of additional cell populations such as neural crest cells. During its septation, the OFT undergoes a rotation (or twisting), which is necessary to connect the pulmonary artery to the right and aorta to the left ventricle.

From the molecular standpoint, its deceptively simple tubular morphology is different at the level of gene expression resulting in regionalization along the proximo-distal and supero-inferior axis. The present study showed that the lipid sensor PPARγ (peroxisome proliferator–activated receptor gamma, well known from adult studies) is expressed in future subpulmonary myocardium in the inferior wall of the outflow tract and that the gene network related to its signalling cascade is regulated by the transcription factor TBX1 (haploinsifficiency of which is known to be associated with 22q deletion syndrome and outflow tract defects). Experimental modulation of PPARγ signalling revealed that it is required for addition of future subpulmonary myocardium and normal arterial pole development, being upregulated in the pulmonary part of the outflow tract while it is negatively regulated in the subaortic myocardium superiorly by the NOTCH signalling pathway via the non-canonical Notch ligand Dlk1. The authors concluded that Pparγ is a regulator of regional transcriptional identity in the developing outflow tract, providing new insights into gene interactions involved in congenital heart defects.

In a broader perspective, provided by an editorial comment by Jianbo Wang, an intriguing question was raised as to how a particular diet during pregnancy may influence the occurrence of outflow tract defects. For example, high fat and dietary sugar (common in current Western diet) upregulate PPARγ, which may disturb the positional identity of the individual components resulting in their misalignment. The confirmed players in the outflow tract patterning, notably NOTCH and TBX1 (also studied previously by the Kelly lab) are all part of the puzzle, so the individual bits fit nicely together. These findings thus provide new ground how to possibly test the gene-environment interactions, identifying genotypes with increased susceptibility to dietary excesses and thus chipping away from the block of congenital heart disease cases at present labelled as “unknown origin”. Ultimately, the agonists and antagonists of these signalling pathways are currently being tested as treatment for cancer and metabolic disorders, and could be in theory also used to prevent, in carefully selected cases, some outflow tract defects associated with 22q deletion syndrome.

References


Rammah et al. (Kelly lab, Aix Marseille University, Developmental Biology Institute of Marseille) - DOI: 10.1161/CIRCRESAHA.122.320766

Notes to editor


Professor David Sedmera 
Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic and Institute of Physiology, The Czech Academy of Sciences, Prague, Czech Republic 

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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