Ischemic cardiomyopathy is the leading cause of death in the world and affects approximately 1% to 2%
of the general population. Sphingolipids including ceramides and sphingosine-1-phosphate have been
demonstrated to play roles in myocardial injury. Previous research from the lab showed that SPTLC3-derived
sphingolipids comprise greater than 1/3rd the myocardial sphingolipid pool, a previously underappreciated group
of sphingolipids. SPTLC3, a recently identified subunit of the serine palmitoyltransferase (SPT) enzyme, along
with SPTLC1, synthesizes the SPTLC3-derived or non-canonical sphingolipids, whereas SPTLC2 with SPTLC1
synthesizes canonical sphingolipids. Over-abundance of SPTLC3-derived sphingolipids has been associated
with increased apoptosis in cardiomyocytes and other heart pathologies. Little is known of the induction of the
programmed cell death pathways by these particular sphingolipids. Interestingly, I found that SPTLC3 and
derived sphingolipids showed robust induction in human and mouse ventricle ischemic tissue as compared to
complete absence of SPTLC3 in the non-ischemic control tissues.
Based on my preliminary results, I hypothesize that induction of SPTLC3 increases d16-DHS1P which in
turn promotes formation of an ATG7/P53/Parkin complex by direct binding. This leads to inhibition of Parkin-
mediated mitophagy thereby promoting mitochondria-dependent cell death. Our preliminary data support that
SPTLC3-derived sphingolipids induce formation of a novel complex between ATG7, P53, and Parkin, and we
propose complex formation of this complex mediates apoptosis. Therefore, to test this hypothesis we will
overexpress and/or knockdown SPTLC3 and determine protein-lipid and protein-protein interactions and
whether this complex regulates mitophagy and/or apoptotic pathways.
Second, We hypothesize that cardiomyocyte specific Sptlc3 knockout mice will show improved
cardiovascular health and subsequent increased longevity in ischemia as compared to their control cohorts. To
test our hypothesis, we recently developed a cardiomyocyte specific Sptlc3 null mouse (cSptlc3 KO) line, which
to our knowledge is the first of its kind. We will be performing permanent left anterior descending (LAD) coronary
artery ligation in the cardiomyocyte specific Sptlc3 null mouse (cSptlc3 KO). We will then determine the impact
of SPTLC3 depletion on cardiac sphingolipid profiles, mitophagy/apoptosis, and cardiac structure/function in
ischemia including adverse remodeling.
Understanding the biological activities of the SPTLC3-derived sphingolipids will provide insights and
establish the role of these sphingolipids in cardiac ischemia. This proposal will lay the foundation for further
research on potential targeting of the pathway as an innovative therapeutic option to circumvent ischemia leading
to heart failure and improve patient outcome.