From Endothelium to Lipids, Through microRNAs and PCSK9: A Fascinating Travel Across Atherosclerosis

Lipids and endothelium are pivotal players on the scene of atherosclerosis and their interaction is crucial for the establishment of the pathological processes. The endothelium is not only the border of the arterial wall: it plays a key role in regulating circulating fatty acids and lipoproteins and vice versa it is regulated by these lipidic molecules thereby promoting atherosclerosis. Inflammation is another important element in the relationship between lipids and endothelium. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a fundamental regulator of LDL-C and anti-PCSK9 monoclonal antibodies have been approved for therapeutic use in hypercholesterolemia, with the promise to subvert the natural history of the disease. Moreover, growing experimental and clinical evidence is enlarging our understanding of the mechanisms through which this protein may facilitate the genesis of atherosclerosis, independently of its impact on lipid metabolism. In addition, environmental stimuli may affect the post-transcriptional regulation of genes through micro-RNAs, which in turn play a key role in orchestrating the crosstalk between endothelium and cholesterol. Advances in experimental research, with development of high throughput techniques, have led, over the last century, to a tremendous progress in the understanding and fine tuning of the molecular mechanisms leading to atherosclerosis. Identification of pivotal keystone molecules bridging lipid metabolism, endothelial dysfunction and atherogenesis will provide the mechanistic substrate to test valuable targets for prediction, prevention and treatment of atherosclerosis-related disease.