Executive Summary : | Cardiovascular disease is one of the leading cause of morbidity and mortality
worldwide. The prevalence of cardiovascular disease is on the rise especially
in South Asian population. The pathophysiology of atherosclerosis, which is
the hallmark of these cardiovascular disease is not fully elucidated. There are
various anti-atherogenic molecules in circulation like HDL, adiponectin and
sphingosine 1-phosphate (S1P). But taken individually their anti-atherogenic
effects fail to be significant showing that the interplay between these
molecules needs to be explored in greater detail in order to better
understand their role in atherosclerosis.
Adiponectin, a hormone secreted by adipose tissue has various beneficial
physiological effects. This includes insulin sensitising, anti-apoptotic and antiatherogenic effects. The anti-atherogenic effect exerted by adiponectin on
endothelial cells has been shown to be mediated by caveolin mediated
recruitment of ceramidase which converts intracellular ceramide to
sphingosine. This sphingosine is converted to S1P by sphingosine kinase.
The proposed study explores the role of S1P in mediating the antiatherogenic
effects of adiponectin.
S1P is a physiologically active lipid mediator with proven anti-atherogenic
effects on endothelium. Intracellular S1P needs to move to the extracellular
compartment or the outer leaflet of the plasma membrane to activate the S1P
receptors. This efflux of S1P is mediated by ATP binding cassette transporter
A1 (ABCA1). Through this study we would also like to explore the role of
ABCA1 in regulating the S1P mediated effects of adiponectin. The efflux of
S1P through ABCA1 is regulated by binding of HDL or Apo-A1 to ABCA1
giving an additional layer of complexity. This could also regulate the effects of
adiponectin mediated through S1P. This aspect also will be explored through
this study.
Altogether this study will explore how adiponectin, HDL and S1P causes very
similar anti-atherogenic effects on endothelial cells by acting in a sequential
manner. |
Co-PI: | Dr. Archna Singh, Associate Professor, All India Institute of Medical Sciences (AIIMS), New Delhi, Dr. Ambuj Roy, Additional Professor, All India Institute of Medical Sciences (AIIMS), New Delhi |
Total Budget (INR): | 33,61,600 |
Outcome/Output: | We expect to establish
a novel mechanism for the action of adiponectin on endothelial cells in providing anti-atherogenic effects |