Healing the injured vessel wall using microRNA-facilitated gene delivery

Abstract

C o m m e n t a r y 3 6 9 4jci.org Volume 124 Number 9 September 2014Healing the injured vessel wall using microRNA-facilitated gene delivery Vascular endothelium and injury from percutaneous coronary interventionOver the past 37 years, percutaneous coronary intervention (PCI) has revolutionized patient revascularization care for symptomatic ischemic coronary artery disease by improving myocardial perfusion and clinical outcomes. However, PCI has been considered a double-edged sword due to the endothelial injury and denudation that occurs from a combination of high-pressure balloon inflations and relatively noncompliant stent struts. The vascular response to mechanical endothelial cell (EC) and smooth muscle cell (SMC) injury represents a complex series of molecular and cellular events that involve the orchestration between resident and recruited vascular cells, leukocytes, and progenitor cells that regulate the ensuing neointimal hyperplasia, vascular remodeling, and reendothelialization (1). A range of innovative therapies and mechanical coronary device strategies have evolved to improve the outcomes and response to injury induced as a consequence of these procedures for patients with symptomatic coronary lesions. By 1993, baremetal stents (BMS) were FDA approved in the US. Compared with balloon angioplasty alone, BMS dramatically improved vessel remodeling with reduced restenosis rates and fewer subsequent reinterventions required. The improvements seen with BMS are thought to be primarily due to a reduction in late lumen loss, a process known as negative remodeling (2); however, clinical restenosis rates still occurred in approximately 20% to 30% of patients receiving BMS, in part, due to persistent neointimal hyperplasia (3, 4). A decade later, drug-eluting stents (DES), which release antimitotic drugs, such as sirolimus, paclitaxel, zotarolimus, or everolimus, were developed and potently inhibit SMC proliferation and extracellular matrix generation, resulting in markedly reduced neointimal hyperplasia and an approximately 70% reduction of coronary restenosis compared with BMS (5, 6). Because DES-dependent drug delivery does not discriminate between proliferating vascular SMCs (VSMCs) and ECs, delayed reendothelialization has been considered a major limiting factor for optimal vascular repair and may predispose patients to late thrombotic events (7,8). Indeed, preclinical studies and pathologic evaluation at the time of human autopsy have confirmed a delayed reendothelialization associated with DES (9, 10). Considerable attention has been focused on the possibility of late (30 days to 1 year) and very late (after 1 year) thrombosis associated with DES and whether extended dual antiplatelet therapy (DAPT) reduces this potential thrombotic risk (11-13). DAPT itself may also carry higher bleeding risks over this extended period. Every year, nearly 500,000 patients in the US undergo PCI for symptomatic coronary artery disease, and DES are deployed in at least 75% of these cases (14). As such, identification of...

The role of miR-126 in embryonic angiogenesis, adult vascular homeostasis, and vascular repair and its alterations in atherosclerotic disease

“…Santulli et al [112] constructed an adenoviral vector containing the cyclin-dependent kinase inhibitor CDKN1B gene and four tandem repeats of miR-126. Delivery of this construct to balloon-injured arteries in rats resulted in the complete reendothelialization along with the prevention of unfavorable side effects such as neointima formation, vasoreactivity, and hypercoagulant status [113]. In fact, this construct supports the endothelial-specific vascular remodeling while inhibiting the hyperresponse of VSMCs to vascular injury.…”

Platelet microRNAs and vascular injury

“…Further investigation of the distinct roles of plateletderived miRNAs in various tissues, and even cell types within a particular tissue, is thus warranted. This knowledge can provide insight into therapeutic targets for such vascular processes as micro-and macrovascular complications of diabetes (16) and re-endothelialization and VSMC proliferation after stent placement (17).…”

Stent‐mediated gene and drug delivery for cardiovascular disease and cancer: A brief insight

“…MiRNAs are persuasive regulators of numerous biological events and play a major role in VSMC homeostasis. Hence, they are subjugated as biomarkers that can possibly enable proficient therapeutic targets concerning vascular pathology, thereby circumventing neointimal proliferation and augmented endothelial regeneration after vascular injury …”

“…Hence, they are subjugated as biomarkers that can possibly enable proficient therapeutic targets concerning vascular pathology, thereby circumventing neointimal proliferation and augmented endothelial regeneration after vascular injury. 64,65 Manoeuvring VSMC associated miRNAs presents a new therapeutic option for plaque stabilization and its complications. Studies suggest that miR-143/145 can influence the regulation of the VSMC phenotype.…”