Abstract
Atherothrombosis, a multifactorial and multistep artery disorder, represents one of the main causes of morbidity and mortality worldwide. The development and progression of atherothrombosis is closely associated with age, gender and a complex relationship between unhealthy lifestyle habits and several genetic risk factors. The imbalance between oxidative stress and antioxidant defenses is the main biological event leading to the development of a pro-oxidant phenotype, triggering cellular and molecular mechanisms associated with the atherothrombotic process. The pathogenesis of atherosclerosis and its late thrombotic complications involve multiple cellular events such as inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells (SMCs), extracellular matrix (ECM) alterations, and platelet activation, contributing to chronic pathological remodeling of the vascular wall, atheromatous plague formation, vascular stenosis, and eventually, thrombus growth and propagation. Emerging studies suggest that clotting activation and endothelial cell (EC) dysfunction play key roles in the pathogenesis of atherothrombosis. Furthermore, a growing body of evidence indicates that defective autophagy is closely linked to the overproduction of reactive oxygen species (ROS) which, in turn, are involved in the development and progression of atherosclerotic disease. This topic represents a large field of study aimed at identifying new potential therapeutic targets. In this review, we focus on the major role played by the autophagic pathway induced by oxidative stress in the modulation of EC dysfunction as a background to understand its potential role in the development of atherothrombosis.
Highlights
These data were confirmed in recent studies, secondary messengers, such as diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) which, in turn, lead to an increased concentration of cytosolic calcium [35,36].4 of Principe et al conducted one of the first studies to highlight the key role of free radicals and, in particular, of hydrogen peroxide (H2O2), in platelet activation induced by collagen through significant calcium mobilization [37]
Due to endothelial dysfunction, uncoupled endothelial nitric oxide synthase (eNOS) uncoupling and NADPH oxidase (NOX) activation lead to the overprothe overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which are able to interact with platelets through the adenosine diphosphate (ADP) receptor, triggering the duction of ROS andsignaling
It is widely accepted that the maintenance of the structure and the functionality of the endothelium are crucial in vascular homeostasis, and there is experimental evidence showing that ROS and RNS overproduction is responsible for endothelial dysregulation
Summary
Autophagy is an evolutionary conserved catabolic pathway for bulk degradation that plays a key role in eliminating long-lived proteins, macromolecular aggregates, and damaged intracellular organelles and simultaneously generates an internal nutrient pool of macromolecules needed to support metabolic reactions [18,19] These processes are essential both to maintain cellular homeostasis and to provide a survival mechanism in response to various stressful conditions, such as nutrient deprivation, viral infections, and genotoxic stress [20]. Several studies have shown a clear link between autophagy and a wide array of vascular processes, ranging from angiogenesis to calcification of the vessel wall, as well as in the paracrine regulation of vasoactive substances from the endothelium [23,24] According to this evidence, autophagic dysregulation may be implicated in vascular pathological remodeling and disease processes such as atherosclerosis, leading to EC dysfunction and contributing to the development of inflammation and thrombosis [25,26]. We briefly summarize the role of oxidative stress in atherothrombosis and focus on the link between oxidative stress and defective autophagy in ECs during the atherothrombotic process
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