Elastin-like recombinamer-based devices releasing Kv1.3 blockers for the prevention of intimal hyperplasia: An in vitro and in vivo study

Abstract

Coronary artery disease (CAD) is the most common cardiovascular disorder. Vascular surgery strategies for coronary revascularization (either percutaneous or open) show a high rate of failure because of restenosis of the vessel, due to phenotypic switch of vascular smooth muscle cells (VSMCs) leading to proliferation and migration. We have previously reported that the inhibition of Kv1.3 channel function with selective blockers represents an effective strategy for the prevention of restenosis in human vessels used for coronary angioplasty procedures. However, delivery systems for controlled release of these drugs have not been investigated. Here we tested the efficacy of several formulations of elastin like recombinamers (ELRs) hydrogels to deliver the Kv1.3 blocker PAP-1 in various restenosis models. The dose and time course of PAP-1 release from ELRs click hydrogels was able to inhibit human VSMC proliferation in vitro as well as remodeling of human vessels in organ culture and restenosis in in vivo models. We conclude that this combination of active compound and advanced delivery method could improve the outcomes of vascular surgery in patients.

miR-126 contributes to the epigenetic signature of diabetic vascular smooth muscle and enhances antirestenosis effects of Kv1.3 blockers

“…Both treatments significantly decreased vessel stenosis induced by carotid ligation in BPH mice, albeit PAP-1 treatment seemed to be more potent in all treated animals ( Figure 8 A). The effects of PAP-1 inhibiting remodeling have been previously explored in control BPH/SD animals, with no differences between systemic or local application and no sex-related differences [ 19 ]. Here, we used the local application of PAP-1 after carotid ligation in our VRF model (BPH/HFD mice).…”

“…Weight, blood pressure, fasting blood glucose, intraperitoneal glucose tolerance test (ipGTT), and intraperitoneal insulin tolerance test (ipITT) [ 18 ] were determined (see expanded methods). To induce IH, carotid artery ligation was performed as described [ 19 ]. Four weeks after surgery, animals were euthanized in a CO 2 chamber.…”

“…Fixed arteries were paraffin-embedded to obtain 7-μm sections [ 12 , 19 ]. Vascular remodeling and IH development were determined in Masson trichrome stained sections using well-known descriptors [ 19 , 20 ] (refer Supplemental Figure I and Table 1 ).…”

NOTCH3 as a modulator of vascular disease: a target in elastin deficiency and arterial pathologies

“…Although elastin deficiencies do not lead directly to atherosclerosis, degradation of elastin may allow lipid infiltration into atherosclerotic plaques, leading to the progression of atherosclerosis ( 5 ). Additionally, multiple studies have investigated the use of tropoelastin and elastin-like recombinamers to combat neointimal hyperplasia in vascular grafts and stents ( 6 , 7 ).…”

Silk-Elastin-like Polymers for Acute Intraparenchymal Treatment of the Traumatically Injured Spinal Cord: A First Systematic Experimental Approach

“…Additionally, they are typically degradable and can be used to generate different structures such as particles, fibres, sheets, and porous hydrogel scaffolds for tissue engineering purposes. Finally, it should be noted that ELPs retain most of the mechanical properties of natural elastin and, consequently, display a great elasticity and resistance to fatigue [20][21][22][23][24][25][26][27].…”