Differential phosphoinositide 3-kinase signaling: implications for PTCA?

Abstract

CORONARY REVASCULARIZATION by percutaneous transluminal coronary angioplasty (PTCA) has an ϳ90% success rate immediately posttreatment (5). However, the procedure causes vascular injury by endothelial denudation and stretching of the vascular wall, leading to inward vascular remodeling. Endothelial cell (EC) removal exposes the underlying medial vascular smooth muscle cell (VSMC) layer to circulating growth factors and inflammatory cytokines, including platelet-derived growth factor (PDGF), thrombin, thromboxane A 2 , and adenosine diphosphate released from accumulating platelets (5). PDGF and thrombin are potent stimuli for VSMC proliferation and migration. Adenosine diphosphate binding to the platelet P2Y 12 receptor causes enhanced platelet activation, thereby facilitating further PDGF release, as well as amplification of the response to thromboxane A 2 and thrombin, thus playing a central role in thrombus formation. Balloon dilation stretches the vascular wall, resulting in activation of stretch-activated signaling pathways in medial VSMC and the adventitia, which results in further VSMC migration and proliferation. Consequently, vascular injury associated with PTCA often results in reocclusion of the artery, or restenosis, characterized by neointima formation and constrictive inward remodeling mediated by VSMC migration across the internal elastic lamina, VSMC proliferation, and extracellular matrix deposition.Incidence of restenosis has been reduced from 42 to 32%, and need for target lesion revascularization from 35 to 15%, with the use of bare-metal stents (BMS) compared with PTCA alone, and further decreased by the use of drug-eluting stents (DES). Sirolimus (rapamycin)-and placlitex-eluting stents have shown 90% reduction in restenosis at 1-yr follow-up and 74% reduction at 4-yr follow-up (5), resulting in their widespread use since 2005. However, DES have since then been associated with a 0.5-3.1% incidence of in-stent thrombosis. Although rare, when it does occur, in-stent thrombosis has catastrophic outcomes with incidence of fatal myocardial infarction (MI) between 25 and 65% and non-MI-related fatality of 45-75% (5). Seventy-five percent of these MIs have been associated with late (30 days to 12 mo) or very late (beyond 1 yr) in-stent thrombosis (5). All have been associated with impaired reendothelialization. DES are associated with ϳ5% occurrence of MI or other myocardial death compared with 1.3% with BMS. Furthermore, at 3-6 mo follow-up, all of the BMS were completely reendothelialized, whereas 87% of the Sirolimus DES were not, and 50% contained thrombi (5). Sirolimus has also been shown to directly activate platelets, causing further platelet aggregation and contributing to thrombus formation. Therefore, while current DES attenuate VSMC proliferation and migration, thus preventing restenosis, they also inhibit EC proliferation and migration, thus preventing reendothelialization, and contribute to thrombus formation by activating platelets, which has led to ϳ20% reduction in DES use. Thus sig...

Differential Clinical Responses to Everolimus-Eluting and Paclitaxel-Eluting Coronary Stents in Patients With and Without Diabetes Mellitus

“…17 In contrast, the mechanism of rapamycin is limited to interfering with cellular mitosis, a process tightly regulated by glycosylation-dependent enzymes. 18 Even more unexpected than the observed differences in TLR were the significant interactions present for the relative risks of MI and stent thrombosis between EES and PES according to the presence of diabetes mellitus. Although the increase in restenosis observed in diabetic compared with nondiabetic patients with EES (but not PES) may in part have contributed to its greater rate of MI in this cohort, 19 this mechanism is unlikely to completely explain the loss of the safety benefit for EES in the diabetic group.…”

Randomized Comparison of Everolimus- and Paclitaxel-Eluting Stents

“…A recent pooled patientlevel analysis from the SPIRIT II, SPIRIT III, SPIRIT IV, and COMPARE trials found this interaction to be statistically significant (9). Additional studies are warranted to understand the mechanisms and influence of the glycemic state on the differential vascular responses to rapamycin analogueeluting stents and PES (10,11).…”

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

“…Revascularization procedures such as PTCA and placement of stents cause vascular injury, which exposes VSMCs to growth factors PDGF and thrombin, the 2 potent stimulators of VSMCs proliferation and migration and neointimal formation 23. PDGF induces phosphorylation of MEK and ERK, which then induces phosphorylation of Elk.…”

“…However, drug‐eluting stents presented with an unexpected problem of an increased rate of in‐stent thrombosis (0.5–3.1%),4, 5, 6, 7, 18, 19 which causes a significantly high 6.3% rate of MI and death 18, 20, 21, 22. This led to a 20% reduction in the use of drug‐eluting stents 23. Thus, despite important improvements in PTCA and placement of drug‐eluting stents to treat CAD and MI, restenosis continues to occur in about 10% of patients and in‐stent thrombosis poses a serious threat to patients.…”