Getting to the Heart of the Global Mortality Epidemic: SPT3 in Cardiac Ischemia [online video]

Streaming Media

Original Publication Date


Document Type



5th Annual VCU 3MT® Competition, held on October 18-19, 2019.


Heart failure is the leading cause of mortality worldwide. Sphingolipids including ceramides and sphingosine-1-phosphate have been demonstrated to play roles in myocardial injury leading to heart failure. In general, these lipids are synthesized from serine palmitoyltransferase (SPT) using serine and palmitoyl-CoA as substrates. The standard SPT enzyme exists as a heterodimer of two subunits, Sptlc1 and Sptlc2. When Sptlc1 is paired with a third subunit, Sptlc3, the complex preferentially uses myristoyl-CoA as a substrate, to generate an underappreciated group of atypical sphingolipids. We previously demonstrated that these atypical lipids are a major component of myocardial sphingolipid pools and observed Sptlc3 induction in human and mouse ischemic heart failure samples. This led us to investigate the contribution of Sptlc3, and the atypical sphingolipids synthesized by Sptlc3 to cardiomyocyte apoptosis and ischemic injury, and to assess the potential relevance of Sptlc3 to human heart failure. The results showed apoptosis and atypical sphingolipids in the sphingolipid pool were increased in ischemic samples. Upon knockdown of Sptlc3, we observed reduced apoptosis in ischemic cardiomyocytes. Under hypoxic and ischemic conditions, HIF1α binds the Sptlc3 promoter at multiple consensus sites. We conclude that the Sptlc3-derived sphingolipids are enriched in the myocardium of mice and humans with ischemic heart failure. We propose Sptlc3 is regulated by HIF1α and that the Sptlc3-derived lipids mediate myocardial injury and are potentially viable therapeutic targets.


In 2016, there were 56.9 million deaths worldwide. More than 20% of these deaths were attributed to what is known as Cardiac Ischemia. Cardiac ischemia is when blood flow is restricted from entering a part of the heart. When the blood flow becomes restricted, the heart doesn’t get the nutrients and oxygen required to function normally. Thus, the heart begins to deteriorate and can eventually fail from prolonged ischemia. It has remained the leading cause of death globally in the last 15 years. Although cardiac ischemia can be inherited, diabetes and obesity play a key role in causing cardiac ischemia. Due to this relationship, and the current rise of diabetes and obesity, cardiac ischemia will continue to be the leading cause of death worldwide.

This is where my research comes in. In the last few months, we have directly linked cardiac ischemia with a significant increase of the enzyme SPT3 in both humans and mice. SPT3 essentially makes lipids, a type of fat, that cause cardiac cells to die. This discovery led us to hypothesize that SPT3, and the cell death that it causes in the heart, leads to a vicious cycle. Once the lipids have started to kill heart cells, the heart becomes weak and stressed. We believe that SPT3 is also induced by stress. So, the more heart cells that die, the more SPT3 is localized from other parts of the body to continue the cycle of lipid production and cell death eventually leading to death from cardiac ischemia.

To test this hypothesis, we breed mice which have no SPT3 enzyme in their hearts, and then induce cardiac ischemia. If our hypothesis holds true, we expect these to have a better clinical outcome than their counterparts which still have the SPT3 enzyme.

If our research can prove that the existence of SPT3 in the heart is a contributing factor to heart related death, we could potentially create enzyme inhibitors to turn off SPT3 and reduce the impact of cardiac ischemic deaths worldwide. Not only could we potentially stop the progression of ischemia, but if the cycle of cell death is true, stopping SPT3 could potentially reverse the effects of current ischemic patients and restore the heart back to normal. Those people that dies in 2016 due to cardiac ischemia could have potentially had this reversed.


© The Author