Inhibition of Apoptosis Through Localized Delivery of Rapamycin-Loaded Nanoparticles Prevented Neointimal Hyperplasia and Reendothelialized Injured Artery

Abstract

Background-A significant fraction of vascular smooth muscle cells (VSMCs) undergo rapid apoptosis after balloon angioplasty.In this study, we tested the hypothesis that protecting VSMCs from undergoing apoptosis prevents the cascade of events that lead to intimal hyperplasia. Methods and Results-Rapamycin-loaded gel-like nanoparticles (mean diameter, 54Ϯ5 nm) were infused locally in a rat carotid artery model of vascular injury. The drug has both antiapoptotic and antiproliferative effects on VSMCs and hence was selected for the current study. Localized delivery of nanoparticles sustained the drug level in the target artery for Ͼ2 weeks; demonstrated significant inhibition of hyperplasia (intima/media ratio, 1.5Ϯ0.02 versus 2.7Ϯ0.6; PϽ0.01); and most importantly, reendothelialized the injured artery (endothelium coverage: treated 82% versus control 28%). We also demonstrated inhibition of activation of caspase-3/7 enzymes in the treated artery, preventing VSMCs from undergoing apoptosis and subsequent infiltration of macrophages. Conclusions-It may be postulated that the localized delivery of rapamycin inhibited apoptosis of VSMCs, minimizing the inflammatory response to the injury and, thus, creating conditions conducive to vascular repair (reendothelialization). Unlike stenting, which can lead to thrombosis and increased risk for in-stent restenosis, our approach could eliminate or minimize long-term complications because the injured artery undergoes a natural process of reendothelialization.

Targeted epidermal growth factor receptor nanoparticle bioconjugates for breast cancer therapy

“…Studies conducted by Reddy in controlling cell cycle analysis than native drug in VSMC cells. Approximately 75% of cells treated with rapamycin loaded nanoparticles were arrested in G0/G1 phase, when compared with native rapamycin in solution [55]. Similar results were found in case of dexamethasone loaded nanoparticles which had a higher proportion of cells in the G0/G1 phase than the cells treated with drug in solution [47].…”

Cholesterol Esterification as a Mediator of Proliferation of Vascular Smooth Muscle Cells and Peripheral Blood Mononuclear Cells during Atherogenesis

“…mTOR is a serine/threonine kinase of the phosphoinositide 3-kinase-related kinase family, and its inhibitors, by inactivating important translators of specific mRNA involved in cell cycle progression, lead to growth arrest at G1 phase [12]. In addition, mTOR inhibitors have been shown to downregulate the genes responsible for the induction of apoptosis in VSMCs and macrophages [13]. Accelerated apoptosis of vascular cells produces fibrous cap thinning and, consequently, plaque instability; therefore, these drugs, by slowing down apoptosis, may also contribute to the maintenance of plaque stability.…”

Delayed inhaled carbon monoxide mediates the regression of established neointimal lesions

“…Inhibition of apoptosis signal-regulating kinase 1, which reduced injury induced apoptosis, significantly reduced IH. Reddy et al (25) showed that treatment of balloon injured arteries with rapamycin-loaded nanoparticles inhibited arterial wall apoptosis and improved re-endothelialization and reduced IH. Finally, Skelly et al (26) expressed an attenuated herpes simplex virus which inhibited apoptosis in injured arteries and attenuated IH.…”