Impact of new protein on the assessment of cardiovascular risk – CARDIF1

Plasma concentrations of HDL cholesterol (HDL-C) and its major protein component apolipoprotein (Apo) A-I are strongly inversely associated with cardiovascular risk, leading to the concept that therapy to increase HDL-C and ApoA-I concentrations would be antiatherosclerotic and protective against cardiovascular events. The protective effect of HDL is mostly attributed to its central function in reverse cholesterol transport (RCT), a process whereby excess cell cholesterol is taken up and processed in HDL particles, and is later delivered to the liver for further metabolism and bile excretion. The recent failure of the drug torcetrapib, a cholesteryl ester transfer protein inhibitor that substantially increased HDL-C concentrations, has brought focus on the issues of HDL function in promoting RCT as distinct from HDL-C concentrations. Therefore, robust laboratory assays of HDL functions and/or rate of RCT and validation of the usefulness of these assays for predicting cardiovascular risk and assessing response to therapeutic interventions are critically important and of great interest to cardiovascular clinicians and investigators and clinical chemists.
In this context, we have identified the F1-ATPase-mediated HDL pathway as a new pathway promoting the last step of RCT (i.e. hepatic HDL-C removal). Furthermore, we have recently found that the natural inhibitor IF1 of F1-ATPase, usually expressed in mitochondria, was also circulating in human and mice blood. Since our previous studies observed that exogenous recombinant IF1 could inhibit the F1-ATPase-mediated HDL pathway both on cellular models and on IF1-perfused rat liver, we hypothesized here that the circulating form of IF1 could constitutively modulate HDL metabolism and that its quantification in serum could be useful for predicting cardiovascular risk and assessing response to therapeutic interventions. This hypothesis was partly confirmed by our preliminary data showing a positive correlation between circulating IF1 and HDL levels in a cohort of 275 male subjects taken from the general population.
In this project, we propose:
1) To explore in a large control-case epidemiological study the relevance of circulating IF1 level in the evaluation of the cardiovascular risk.
2) To explore the role of IF1 in experimental models of RCT and atherogenesis
3) To standardize ELISA Assay for IF1 quantification in serum and elaborate therapeutic approaches
The overall objective is to validate IF1 as a new biological circulating marker that reflects the functionality of HDL and not only their circulating level and might be better predictor of cardiovascular risk. This might lead to the development of a new kit for functional HDL levels that may be used in clinical biochemistry laboratories for predicting of cardiovascular risk and treatment’s choice. Finally, regarding the highly competitive field of HDL therapy, this research project might conduce to the discovery of a new way increasing functional HDL, for the development of new drugs as a treatment for cardiovascular disease.