DOI
https://doi.org/10.25772/WJZA-Z415
Author ORCID Identifier
https://orcid.org/0000-0003-0735-9131
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Human Genetics
First Advisor
Dr. L. Ashley Cowart
Second Advisor
Dr. Fadi Salloum
Third Advisor
Dr. Swadesh Das
Fourth Advisor
Dr. Zheng Fu
Fifth Advisor
Dr. Devanand Sarkar
Sixth Advisor
Dr. Brian Wattenberg
Abstract
Myocardial disease continues to be the leading cause of death globally, underscoring the urgent need for new therapeutic strategies. Sphingolipids play a critical role in maintaining cardiac homeostasis, and their dysregulation can contribute to myocardial disease, heart failure, and death. Sphingolipids are critical molecules involved in various cellular processes in the heart, including hypertrophy, fibrosis, atherosclerosis, inflammation, and cellular death pathways. Although inhibiting the de novo synthesis pathway of sphingolipids has been investigated as a therapeutic approach to reduce cardiac lipotoxicity, targeting individual sphingolipid species has emerged as a more promising strategy. For example, clinically, serum levels of ceramide C16:0, and C24:0 can predict adverse cardiac events such as myocardial infarction, better than traditional risk factors. This dissertation aims to advance our understanding of sphingolipids in cardiac disease by investigating the role of less-studied sphingolipids in ischemic heart failure and diabetic cardiomyopathy.
The first project focuses on the impact of the serine palmitoyltransferase enzyme long chain base subunit 3 (SPTLC3) and SPTLC3-derived sphingolipids with a 16-carbon backbone in the context of ischemic heart failure, the most common cardiac disease, and the current leading cause of death globally. Results from this study demonstrate that SPTLC3 is induced in humans with ischemic heart failure and a mouse model of ischemic heart failure with concomitant increase of d16-dihydrosphingosine and d16-dihydrosphingosine-1-phosphate. Under ischemic conditions, SPTLC3 is directly regulated by HIF1α, revealing the first non-sphingolipid related regulatory mechanism of SPTLC3. SPTLC3 and the SPTLC3-mimetic d16-dihydrosphingosine are pro-apoptotic signalers in cardiomyocytes. Mice with cardiomyocyte-specific deletion of SPTLC3 more frequently survive to the humane endpoint and have an ameliorated phenotype than the wildtype cohort in a murine model of ischemic heart failure. This effect was mediated by impaired complex I activity of the electron transport chain in the absence of SPTLC3.
The second project investigates the role of ceramide synthase 5 in a murine model of diabetic cardiomyopathy, a unique form of cardiomyopathy causing heart failure in the absence of conventional risk factors such as hypertension, valvular disease, and coronary artery disease. Results from this study demonstrate that mice lacking ceramide synthase 5 in their cardiomyocytes are protected from diet-induced obesity, impaired glucose tolerance and insulin sensitivity. These mice also have reduced levels of ceramide C16 and sphingomyelin C14 compared to wildtype mice on the high fat diet. The CerS5 knockout mice on high fat diet are protected from excess lipidated LC3-II, suggesting that diabetic cardiomyopathy and/or obesity may be in part caused by excessive macroautophagy.
These novel findings provide new insights for the role of sphingolipids in potential therapeutic strategies for myocardial disease.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-8-2023