Significant difference between sirolimus and paclitaxel nanoparticles in anti-proliferation effect in normoxia and hypoxia: The basis of better selection of atherosclerosis treatment

Abstract

Compared with paclitaxel, sirolimus has been more used in the treatment of vascular restenosis gradually as an anti-proliferative drug, but few basic studies have elucidated its mechanism. The anti-proliferative effects of sirolimus or paclitaxel have been demonstrated by numerous studies under normoxia, but few studies have been achieved focusing hypoxia. In this study, porcine carotid artery injury model and classical cobalt chloride hypoxia cell model were established. Sirolimus nanoparticles (SRM-NPs), paclitaxel nanoparticles (PTX-NPs) and blank nanoparticles (Blank-NPs) were prepared respectively. The effect of RPM-NPs on the degree of stenosis, proliferative index and the expression of PCNA after 28 days of porcine carotid artery injury model was evaluated. Compared with saline group and SRM groups, SRM-NPs group suppressed vascular stenosis, proliferative index and the expression of PCNA ( P < 0.01 and P < 0.05). Endothelial cell (EC) and smooth muscle cell (SMC) were pre-treated with cobaltous chloride, followed by SRM-NPs, PTX-NPs, Blank-NPs or PBS control treating, the effects on cell proliferation, HIF-1 expression and glycolysis were detected. SRM-NPs could inhibit EC and SMC proliferation under hypoxia, while PTX-NPs couldn't ( P < 0.001). Significant differences between sirolimus and paclitaxel NPs in anti-proliferation effect under normoxia and hypoxia may due to the different inhibitory effects on HIF-1α expression and glycolysis. In conclusion, these results suggest that sirolimus can inhibit the proliferation of hypoxic cells more effectively than paclitaxel. These observations may provide a basis for understanding clinical vascular stenosis therapeutic differences between rapamycin and paclitaxel.

Cardiovascular Stents: A Review of Past, Current, and Emerging Devices

“…The structure of the first generation of DESs was based on a stainless-steel platform coated with a drug-eluting durable polymer [6,23,45] (Figure 3). Such devices allow localized elution over the course of a month of neointimal inhibiting drugs, such as sirolimus and paclitaxel, which have antiproliferative effects [46][47][48][49]. DESs were mainly adopted as a solution for in-stent restenosis, a major problem associated with the stenting procedure [52].…”

Nanotechnology for Targeted Therapy of Atherosclerosis

“…In vivo analysis indicated the drug accelerated atherosclerosis increasing the size of the necrotic areas. Another example is a study that compared the effect of anti-proliferative drugs used in vascular restenosis treatment ( Chen et al, 2021 ). Although sirolimus and paclitaxel nanoparticles both exert anti-proliferation effects under normoxia conditions, sirolimus nanoparticle showed a significantly higher effect under the hypoxia condition.…”

MFN2 Prevents Neointimal Hyperplasia in Vein Grafts via Destabilizing PFK1

“…Inhibition of aerobic glycolysis to reserve the Warburg effect has shown beneficial outcomes in alleviating pulmonary hypertension, post-injury restenosis, and atherosclerosis in experimental models. [15][16][17] Despite the centrality of the Warburg effect to VSMC activation, the definite molecular basis of the effect remains unclear. MFN2 (mitofusin 2), an outer mitochondrial membrane protein, serves primarily as mediating fusion of the outer membrane to maintain mitochondrial morphology and function.…”