Novel potential targets for prevention of arterial restenosis: insights from the pre-clinical research

Abstract

Restenosis is the pathophysiological process occurring in 10-15% of patients submitted to revascularization procedures of coronary, carotid and peripheral arteries. It can be considered as an excessive healing reaction of the vascular wall subjected to arterial/venous bypass graft interposition, endarterectomy or angioplasty. The advent of bare metal stents, drug-eluting stents and of the more recent drug-eluting balloons, have significantly reduced, but not eliminated, the incidence of restenosis, which remains a clinically relevant problem. Biomedical research in pre-clinical animal models of (re)stenosis, despite its limitations, has contributed enormously to the identification of processes involved in restenosis progression, going well beyond the initial dogma of a primarily proliferative disease. Although the main molecular and cellular mechanisms underlying restenosis have been well described, new signalling molecules and cell types controlling the progress of restenosis are continuously being discovered. In particular, microRNAs and vascular progenitor cells have recently been shown to play a key role in this pathophysiological process. In addition, the advanced highly sensitive high-throughput analyses of molecular alterations at the transcriptome, proteome and metabolome levels occurring in injured vessels in animal models of disease and in human specimens serve as a basis to identify novel potential therapeutic targets for restenosis. Molecular analyses are also contributing to the identification of reliable circulating biomarkers predictive of post-interventional restenosis in patients, which could be potentially helpful in the establishment of an early diagnosis and therapy. The present review summarizes the most recent and promising therapeutic strategies identified in experimental models of (re)stenosis and potentially translatable to patients subjected to revascularization procedures.

Electron-Transfer/Higher-Energy Collision Dissociation (EThcD)-Enabled Intact Glycopeptide/Glycoproteome Characterization

“…While the underlying mechanisms have been studied from multiple perspectives [69, 70], the N- glycoproteomics has not been very well characterized, despite that N- glycosylation is critical for correct folding, stability and mediating cell attachment [71]. Extracellular matrix (ECM) proteins has long been implicated in the pathogenesis of restenosis, and the fact that more than 90% of ECM proteins are glycosylated makes it more relevant to study carotid artery glycoproteomics [71, 72].…”

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

“…This leads to i ) the differentiation of intima-infiltrated monocytes into macrophages, causing them to accumulate cholesterol, become foam cells and eventually form a lipid core, and ii ) the phenotypic modulation of smooth muscle cells, switching them from a contractile to a synthetic phenotype to promote neointimal hyperplasia. The treatment of symptomatic atherosclerosis typically involves an angioplasty with stent placement but this procedure further damages the vascular endothelium and frequently triggers thrombosis and restenosis [1]. Thus, endothelial protection and repair remain key processes to consider when developing strategies to help prevent atherosclerosis and its complications [2].…”

Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury–Induced Neointimal Hyperplasia

“…Although the use of drug-eluting stents significantly reduces the incidence of restenosis, these drugs have not completely eliminated the occurrence of neointima. 2 A recent prospective study has shown that in patients treated with percutaneous coronary intervention, there is no significant difference in the 6-year rates of death, spontaneous myocardial infarction, quality of life, stroke, or hospitalization for unstable angina between patients receiving drug-eluting stents and those receiving contemporary bare-metal stents. 3 Moreover, managing drug-eluting stent-associated in-stent restenosis becomes an emerging challenge in clinical practice.…”

“…3 Moreover, managing drug-eluting stent-associated in-stent restenosis becomes an emerging challenge in clinical practice. [4][5][6] Therefore, development of new therapeutic options by searching for new biological targets 2 and pharmacological agents 7 is still required. An adequate rate of ribosome biogenesis is essential for cell proliferation to meet the increased demand for protein synthesis.…”