RATIONALE:microRNAs (miRNAs) modulate gene expression by repressing translation of targeted genes. Previous work has established a role for miRNAs in regulating vascular smooth muscle cell (VSMC) ...activity. Whether circular RNAs are involved in the modulation of miRNA activity in VSMCs is unknown.
OBJECTIVE:We aimed to identify circular RNAs interacting with miRNAs enriched in VSMCs and modulating the cells’ activity.
METHODS AND RESULTS:RNA sequencing and bioinformatics identified several circular RNAs enriched in VSMCs; however, only one, possessing multiple putative binding sites for miR-145, was highly conserved between mouse and man. This circular RNA gemmed from alternative splicing of Lrp6 (lipoprotein receptor 6), a gene highly expressed in vessels and implicated in vascular pathologies and was thus named circ_Lrp6. Its role as a miR-145 sponge was confirmed by determining reciprocal interaction through RNA immunoprecipitation, stimulated emission depletion microscopy, and competitive luciferase assays; functional inhibition of miR-145 was assessed by measuring expression of the target genes ITGβ8 (integrin-β8), FASCIN (fascin actin-bundling protein 1), KLF4 (Kruppel-like factor 4), Yes1 (YES proto-oncogene 1), and Lox (lysyl oxidase). The interaction was preferentially localized to P-bodies, sites of mRNA degradation. Using loss- and gain-of-function approaches, we found that circ_Lrp6 hindered miR-145-mediated regulation of VSMC migration, proliferation, and differentiation. Differential expression of miR-145 and circ_Lrp6 in murine and human vascular diseases suggests that the ratio of circ_Lrp6 bound to miR-145 versus unbound could play a role in vascular pathogenesis. Viral delivery of circ_Lrp6 shRNA prevented intimal hyperplasia in mouse carotids.
CONCLUSIONS:circ_Lrp6 is an intracellular modulator and a natural sponge for miR-145, counterbalancing the functions of the miRNA in VSMCs.
RATIONALE:MicroRNAs (miRNAs, miRs) are small noncoding RNAs that modulate gene expression by negatively regulating translation of target genes. Although the role of several miRNAs in vascular smooth ...muscle cells (VSMCs) has been extensively characterized, the function of miRNA-128-3p (miR-128) is still unknown.
OBJECTIVE:To determine if miR-128 modulates VSMC phenotype and to define the underlying mechanisms.
METHODS AND RESULTS:We screened for miRNAs whose expression is modulated by an altered DNA methylation status in VSMCs, and among the hits, we selected miR-128. We found that miR-128 was expressed in various tissues, primary murine cells, and pathological murine and human vascular specimens. Through gain- and loss-of-function approaches, we determined that miR-128 affects VSMC proliferation, migration, differentiation, and contractility. The alterations of those properties were dependent upon epigenetic regulation of key VSMC differentiation genes; notably, Kruppel-like factor 4 was found to be a direct target of miR-128 and able to modulate the methylation status of the pivotal VSMC gene myosin heavy chain 11 (Myh11). Finally, in vivo lentiviral delivery of miR-128 prevented intimal hyperplasia in a mouse model of carotid restenosis without modifying vital cardiovascular parameters.
CONCLUSION:miR-128 is a critical modulator of VSMCs and is regulated by epigenetic modifications upon stress. Its modulation in the context of disease could be exploited for therapeutic purposes.
Background The PETTICOAT (Provisional ExTension to Induce COmplete ATtachment) technique may be employed during endovascular treatment of type B aortic dissection (TBD) using self-expandable bare ...stents distal to the covered stent graft placed over the proximal entry tear. The aim of this study is to evaluate the volume changes of the true (TL) and false lumen (FL) on computed tomography (CT) scans. Methods Since 2005, 25 selected patients received endovascular treatment for complicated TBD with the PETTICOAT technique employing the Zenith Dissection Endovascular System (William Cook Europe, Bjaerverskov, Denmark). Indications to the use of the PETTICOAT technique were the evidence of clinical manifest dynamic malperfusion in five cases (20%) and/or radiologic evidence of TL collapse in 20 cases (80%). Five patients were treated within 2 weeks from onset, 13 patients between 2 weeks and 3 months, and seven patients over 3 months after the initial acute event. The volumetric analysis of the changes of TL and FL obtained from CT scan performed before endovascular treatment of TBD, postoperatively and yearly thereafter were analyzed using the OsiriX software v 3.9 (Pixmeo sarl, Bernex, Switzerland). Results Initial clinical (30 days) and midterm clinical success was observed in 21 cases (84%) and in 23 cases (92%), respectively. The volumes of the aortic TL and FL were evaluated at 30 days and midterm follow-up (mean, 38 ± 17 months). The following TL volumes were recorded: baseline 84 ± 29 cm3 , postoperative 167 ± 31 cm3 (+98%), 1 year 193 ± 46 cm3 (+131%), and 2 years 216 ± 54 cm3 (+140%). The following FL volumes were recorded: baseline 332 ± 86 cm3 , postoperative 286 ± 85 cm3 (−14%), 1 year 233 ± 81 cm3 (−30%), and 2 years 248 ± 112 cm3 (−32%). Progressive remodeling of the TL was recorded over time in both thoracic and abdominal segments with shrinkage of the FL mainly in the thoracic segment. Conclusions These data provide insight into potential therapeutic benefit of the PETTICOAT technique. A significant immediate increase in TL could be achieved with resolution of all cases of dynamic malperfusion and TL collapse. A different behavior of volumes in the thoracic and abdominal segments was observed.
Neurologic deficit after endovascular treatment of the thoracic aorta is a complication reported with variable frequency that may be associated with severe morbidity and mortality. The mechanism of ...spinal cord ischemia appears to be multifactorial and remains ill-defined. We reviewed our experience to investigate the determinants of paraplegia after stent-graft repair of the thoracic aorta, identify patients at risk, and assess the effectiveness of ancillary techniques.
Over a 5-year period (June 1999 to December 2004), 103 patients underwent elective endovascular repair of the thoracic aorta at a university referral center. Indications for treatment were atherosclerotic aneurysms in 88 patients, chronic type B dissection in 10 patients, and penetrating aortic ulcer in 5 patients. Four of the 103 patients affected with thoracoabdominal aortic aneurysms had hybrid procedures and were excluded from the cumulative analysis. Twelve patients with zone 0 and zone 1 aortic arch aneurysms were operated on with synchronous or staged surgical aortic debranching. Preoperative cerebrospinal fluid (CSF) drainage was instituted in seven selected patients. Neurologic deficits were assessed by an independent neurologist and classified as immediate or delayed. Patient demographics and perioperative factors related to the endovascular procedure were evaluated by using univariate statistical analyses.
A primary technical success was achieved in 94 patients (94.9%). At a mean follow-up of 34 ± 14 months, a midterm clinical success was obtained in 90 patients (90.9%). Four patients (4.04%) had delayed neurologic deficit that completely resolved after the institution of CSF drainage, steroids administration, and arterial pressure pharmacologic adjustment. None of the four patients who underwent hybrid procedures for thoracoabdominal aortic aneurysms had paraplegia or paraparesis. Univariate analyses identified only a perioperative lowest mean arterial pressure (MAP) of <70 mm Hg as a significant risk factor (P < .0001).
Perioperative hypotension (MAP <70 mm Hg) was found to be a significant predictor of spinal cord ischemia; hence, careful monitoring and prompt correction of arterial pressure may prevent the development of paraplegia. When the latter occurred, reduction of the CSF pressure by drainage was useful. Patients with a previous or synchronous abdominal aortic repair may also benefit from CSF drainage as a perioperative adjunct.
Objective The aim of this study was to assess the safety and short-term effectiveness of a novel hybrid vascular graft used to address renal revascularization during open thoracoabdominal aortic ...aneurysm (TAAA) repair, performing a sutureless distal anastomosis. Methods Between 2012 and 2013, 25 patients (16 men; mean age, 66 ± 8 years) underwent revascularization of one (24 patients) or both (one patient) renal arteries with the Gore Hybrid Vascular Graft (GHVG; W. L. Gore and Associates, Flagstaff, Ariz) during open TAAA repair. Specific indications included remote location of the ostium of the renal artery, severe atherosclerotic wall degeneration, focal dissection, and stenosis. All surviving patients underwent computed tomography angiography and follow-up visit at 1 month. Preoperative characteristics, intraoperative data, and short-term results were compared with those of 49 concurrent TAAA patients operated on within the same period by standard renal revascularization (SRR) techniques. Results All GHVG target renal vessels (26 of 26) were successfully revascularized without technical concerns. No significant differences were found between GHVG and SRR groups in preoperative and intraoperative data, except for a relative prevalence of aortic dissection (28% vs 6%; P = .026) and renal artery stenosis (44% vs 12%; P = .003) in the GHVG group and for intraoperative renal bare stenting that was predominantly used in the SRR group (12% vs 28%; P = .036). The 30-day mortality was 4% in both groups. Postoperative acute renal failure (doubling of creatinine level and creatinine level >3.0 mg/dL) occurred in two GHVG patients (8%) and seven SRR patients (14%; P = NS). Perioperative peak decrease of estimated glomerular filtration rate was lower in the GHVG group (26 ± 18 mL/min/1.73 m2 vs 37 ± 22 mL/min/1.73 m2 ; P = .034). At 1-month computed tomography angiography, renal artery patency was 92% for the GHVG vessels, 91% for the contralateral to GHVG renal vessels, and 92% for the SRR group arteries. No GHVG-related complications requiring reintervention or cases of new-onset renal failure requiring dialysis were observed at follow-up. Conclusions Renal revascularization during open TAAA repair by the GHVG with distal sutureless anastomosis is feasible, especially in cases of aortic dissection, remote location of the renal vessel, and severe atherosclerotic disease of the ostium. Short-term results are satisfactory, at least comparable to those of SRR. Larger series and longer follow-up are needed to assess clinical advantages and durability of this new device.
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