Oxylipin Signaling in Congenital Heart Disease

Project summary
Congenital heart defects (CHD) constitute the most common type of congenital defect in humans,
however the causes for CHD in most cases are unknown. Lipoxygenase-derived oxylipins are a
complex and poorly characterized class of highly oxidized, polyunsaturated fatty acid-derived bioactive
lipids with key biological activities. We recently found a link between oxylipin signaling, human
cardiovascular development and CHD. This finding is critical not only because of the existing gap in
knowledge, but also because oxylipins are strongly dietary-dependent. Our preliminary data suggests
lipoxygenases and their oxylipin products dramatically modulate cardiogenic mesoderm formation in
human cardiac differentiation model, and their loss leads to CHD in mice. Our central hypothesis is
that endogenous uncharacterized oxylipins are critical regulators of cardiogenic mesoderm specification
and heart morphogenesis through cross-talk with the Wnt signaling pathway. Our objective is to
provide insight into lipoxygenase and oxylipin signaling pathways during cardiac development and
determine their contribution to mechanisms of CHD. Our Specific aims are: (1) Determine the
molecular and cellular mechanisms of oxylipin signaling in human cardiogenic mesoderm specification.
(2) Investigate the role of oxylipins in cardiac extracellular matrix organization in a human stem cell-
derived cardiac organoid model. (3) Evaluate the contribution of oxylipin signaling to congenital heart
defects in mice. Approach: We will study oxylipin function in human pluripotent stem cell-derived
cardiogenic mesoderm and in a 3D cardiac organoid model by combining LC-MS lipidomics, cell and
molecular biology and biochemical methods. We will also employ lipoxygenase knockout mice and
oxylipin dietary restriction to study oxylipins in cardiac development in vivo in mouse embryos.
Significance: This work addresses a major gap in knowledge by exploring the biological roles of
oxylipins in cardiac development, and mechanisms underlying their newly discovered links to CHD. We
also offer a novel potential link between diet and congenital heart defects with significant implications
for CHD prevention. Finally, we offer the potential to discover new therapies for treatment by identifying
druggable targets and signaling networks. Innovation: We will explore for the first time the key
molecular mechanisms linking lipoxygenases, oxylipins and cardiac development signaling networks in
human and mouse tissues. We will also establish a new model of cardiac development that integrates
the role of these environmental lipids with developmental molecular networks. Impact: This project will
dramatically expand knowledge of oxylipin biology in cardiac development, help develop strategies to
prevent and potentially treat CHD, and develop new tools for the study of oxylipins in human biology.

Grant Number: 5R01HL151505-05
NIH Institute/Center: NIH
Principal Investigator: Aitor Aguirre