Molecular aspects of atherogenesis: new insights and unsolved questions.
The development of atherosclerotic disease results from the interaction between environment and genetic make up. A key factor in atherogenesis is the oxidative modification of lipids, which is involved in the recruitment of mononuclear leukocytes to the arterial intima--a process regulated by several groups of adhesion molecules and cytokines. Activated leukocytes, as well as endothelial mitochondria, can produce reactive oxygen species (ROS) that are associated with endothelial dysfunction, a cause of reduced nitric oxide (NO) bioactivity and further ROS production. Peroxisome proliferator-activated receptors (PPAR) and liver X receptors (LXR) are nuclear receptors significantly involved in the control of lipid metabolism, inflammation and insulin sensitivity. Also, an emerging role has been suggested for G protein coupled receptors and for the small Ras and Rho GTPases in the regulation of the expression of endothelial NO synthase (eNOS) and of tissue factor, which are involved in thrombus formation and modulation of vascular tone. Further, the interactions among eNOS, cholesterol, oxidated LDL and caveola membranes are probably involved in some molecular changes observed in vascular diseases. Despite the relevance of oxidative processes in atherogenesis, anti-oxidants have failed to significantly improve atherosclerosis (ATS) prevention, while statins have proved to be the most successful drugs.
Puddu
Giovanni Maria
GM
Department of Internal Medicine and Aging, S. Orsola-Malpighi Hospital, Bologna, Italy.
Cravero
Eleonora
E
Arnone
Giorgia
G
Muscari
Antonio
A
Puddu
Paolo
P
D000818:Animals; D001158:Arteries / Q000378:metabolism; D050197:Atherosclerosis / Q000473:pathology*; D002448:Cell Adhesion; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D000071518:Liver X Receptors; D008928:Mitochondria / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D010100:Oxygen / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D007328:Insulin; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D009569:Nitric Oxide; D013925:Thromboplastin; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen