Alteration of actin dependent signaling pathways associated with membrane microdomains in hyperlipidemia

Membrane microdomains represent dynamic membrane nano-assemblies enriched in signaling molecules suggesting their active involvement in not only physiological but also pathological molecular processes. The hyperlipidemic stress is a major risk factor of atherosclerosis, but its exact mechanisms of action at the membrane microdomains level remain elusive. The aim of the present study was to determine whether membrane-cytoskeleton proteome in the pulmonary tissue could be modulated by the hyperlipidemic stress, a major risk factor of atherosclerosis.

High resolution mass spectrometry based proteomics analysis was performed for detergent resistant membrane microdomains isolated from lung homogenates of control, ApoE deficient and statin treated ApoE deficient mice. The findings of the study allowed the identification with high confidence of 1925 proteins, 291 of which were found significantly altered by the modified genetic background, by the statin treatment or both conditions. Principal component analysis revealed a proximal partitioning of the biological replicates, but also a distinct spatial scattering of the sample groups, highlighting different quantitative profiles. The statistical significant over-representation of Regulation of actin cytoskeleton, Focal adhesion and Adherens junction Kyoto Encyclopedia of Genes and Genomes signaling pathways was demonstrated through bioinformatics analysis. The three inter-relation maps comprised 29 of regulated proteins, proving membrane-cytoskeleton coupling targeting and alteration by hyperlipidemia and/or statin treatment.

The findings of the study allowed the identification with high confidence of the main proteins modulated by the hyperlipidemic stress involved in the actin-dependent pathways. Our study provides the basis for future work probing how the protein activities at the membrane-cytoskeleton interface are dependent upon genetic induced hyperlipidemia.