Cardiovascular disease is one of the leading cause of morbidity and mortalityworldwide. The prevalence of cardiovascular disease is on the rise especiallyin South Asian population. The pathophysiology of atherosclerosis, which isthe hallmark of these cardiovascular disease is not fully elucidated. There arevarious anti-atherogenic molecules in circulation like HDL, adiponectin andsphingosine 1-phosphate (S1P). But taken individually their anti-atherogeniceffects fail to be significant showing that the interplay between thesemolecules needs to be explored in greater detail in order to betterunderstand their role in atherosclerosis.Adiponectin, a hormone secreted by adipose tissue has various beneficialphysiological effects. This includes insulin sensitising, anti-apoptotic and antiatherogenic effects. The anti-atherogenic effect exerted by adiponectin onendothelial cells has been shown to be mediated by caveolin mediatedrecruitment of ceramidase which converts intracellular ceramide tosphingosine. This sphingosine is converted to S1P by sphingosine kinase.The proposed study explores the role of S1P in mediating the antiatherogeniceffects of adiponectin.S1P is a physiologically active lipid mediator with proven anti-atherogeniceffects on endothelium. Intracellular S1P needs to move to the extracellularcompartment or the outer leaflet of the plasma membrane to activate the S1Preceptors. This efflux of S1P is mediated by ATP binding cassette transporterA1 (ABCA1). Through this study we would also like to explore the role ofABCA1 in regulating the S1P mediated effects of adiponectin. The efflux ofS1P through ABCA1 is regulated by binding of HDL or Apo-A1 to ABCA1giving an additional layer of complexity. This could also regulate the effects ofadiponectin mediated through S1P. This aspect also will be explored throughthis study.Altogether this study will explore how adiponectin, HDL and S1P causes verysimilar anti-atherogenic effects on endothelial cells by acting in a sequentialmanner.
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