Cardiovascular disease (CVD) remains the leading cause of death worldwide. High-density lipoprotein (HDL) is traditionally considered “good” cholesterol due to its role in reverse cholesterol transport; however, emerging evidence suggests it has additional protective functions. Among its bioactive components, sphingosine-1-phosphate (S1P) has been identified as a mediator of cardioprotective and metabolic effects. In parallel, the recognition of atherosclerosis as an immune-mediated process has sparked interest in autoantibodies against HDL or its primary protein, apolipoprotein A1 (apoA1), as these may impair HDL function. This thesis summarises a body of research with two aims: (i) to investigate the molecular and functional roles of HDL and its S1P component in providing cardiac and metabolic protection; and (ii) to explore the impact of anti-apoA1 autoantibodies, particularly in populations at increased cardiovascular risk, such as people living with HIV.
A combination of in vitro, ex vivo and in vivo experimental models was used to study HDL-S1P signalling in cardioprotection and in insulin secretion by pancreatic β-cells. Translational studies were conducted to compare the composition and function of HDL in patients with type 2 diabetes and in healthy controls. Finally, in a case-control study I examined the levels and implications of anti-apoA1 autoantibodies in HIV-infected individuals. The key results of my chosen articles are listed below:
HDL induced STAT3 activation in cardiomyocytes, mediated by S1P, conferring protection against doxorubicin-induced toxicity.
In murine infarction models, reconstituted HDL enriched with S1P demonstrated strong cardioprotective effects.
Patients with type 2 diabetes exhibited reduced HDL-S1P content and impaired HDL cardioprotective function.
In pancreatic β-cells, HDL-S1P promoted insulin secretion, underscoring metabolic benefits beyond cardiovascular protection.
Elevated circulating anti-apoA1 autoantibody levels were observed in people living with HIV, correlating with systemic inflammation, altered kynurenine metabolism, and markers of cardiovascular dysfunction.
This body of work emphasises the pivotal function of HDL-S1P in protecting against cardiometabolic disease, thereby supporting therapeutic strategies that target HDL functionality. It also identifies anti-apoA1 autoantibodies as potential biomarkers of cardiovascular risk, particularly in vulnerable populations, such as people living with HIV. Together, these findings bridge the gap between molecular mechanisms and clinical implications, emphasising the dual importance of HDL biology and autoimmunity in CVD.
