scholarly journals Systems Approach to Discovery of Therapeutic Targets for Vein Graft Disease PPARα Pivotally Regulates Metabolism, Activation, and Heterogeneity of Macrophages and Lesion Development

Circulation ◽  
2021 ◽  
Author(s):  
Julius L. Decano ◽  
Sasha A. Singh ◽  
Cauê Gasparotto Bueno ◽  
Lang Ho Lee ◽  
Arda Halu ◽  
...  
Keyword(s):  
Single Cell ◽  
Vein Graft ◽  
Graft Failure ◽  
Systems Approach ◽  
Therapeutic Targets ◽  
Sphingolipid Metabolism ◽  
Peroxisome Proliferator ◽  
Matrix Remodeling ◽  
Lesion Development ◽  
Vein Graft Failure

Background: Vein graft failure remains a common clinical challenge. We applied a systems approach in mouse experiments to discovering therapeutic targets for vein graft failure. Methods: Global proteomics and high-dimensional clustering on multiple vein graft tissues were used to identify potential pathogenic mechanisms. The peroxisome proliferator-activated receptors (PPARs) pathway served as an example to substantiate our discovery platform. In vivo mouse experiments with macrophage-targeted PPARα siRNA and the novel, selective activator pemafibrate demonstrate the role of PPARα in the development and inflammation of vein graft lesions. In vitro experiments further included metabolomic profiling, qPCR, flow cytometry, metabolic assays, and single-cell RNA-sequencing on primary human and mouse macrophages. Results: We identified changes in the vein graft proteome associated with immune responses, lipid metabolism regulated by the PPARs, fatty acid metabolism, matrix remodeling, and hematopoietic cell mobilization. PPARα agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, while gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Metabolomics/lipidomics, functional metabolic assays, and single-cell analysis of cultured human macrophages revealed that PPARα modulates macrophage glycolysis, citrate metabolism, mitochondrial membrane sphingolipid metabolism, and heterogeneity. Conclusions: This study explored potential drivers of vein graft inflammation and identified PPARα as a novel potential pharmacologic treatment for this unmet medical need.

Genetic Therapy for Vein Bypass Graft Disease: Current Perspectives

Vascular ◽  
2004 ◽  
Vol 12 (4) ◽  
pp. 213-217
Author(s):  
Hector F. Simosa ◽  
Michael S. Conte
Keyword(s):  
Vein Graft ◽  
Graft Failure ◽  
Bypass Graft ◽  
Graft Patency ◽  
The United States ◽  
Secondary Patency ◽  
Matrix Remodeling ◽  
Peripheral Ischemia ◽  
Genetic Interventions ◽  
Vein Graft Failure

Although continued progress in endovascular technology holds promise for less invasive approaches to arterial diseases, surgical bypass grafting remains the mainstay of therapy for patients with advanced coronary and peripheral ischemia. In the United States, nearly 400,000 coronary and 100,000 lower extremity bypass procedures are performed annually. The autogenous vein, particularly the greater saphenous vein, has proven to be a durable and versatile arterial substitute, with secondary patency rates at 5 years of 70 to 80% in the extremity.1 However, vein graft failure is a common occurrence that incurs significant morbidity and mortality, and, to date, pharmacologic approaches to prolong vein graft patency have produced limited results. Dramatic advances in genetics, coupled with a rapidly expanding knowledge of the molecular basis of vascular diseases, have set the stage for genetic interventions. The attraction of a genetic approach to vein graft failure is based on the notion that the tissue at risk is readily accessible to the clinician prior to the onset of the pathologic process and the premise that genetic reprogramming of cells in the wall of the vein can lead to an improved healing response. Although the pathophysiology of vein graft failure is incompletely understood, numerous relevant molecular targets have been elucidated. Interventions designed to influence cell proliferation, thrombosis, inflammation, and matrix remodeling at the genetic level have been described, and many have been tested in animal models. Both gene delivery and gene blockade strategies have been investigated, with the latter now reaching the stage of advanced clinical trials.

scholarly journals Torsion Does Not Affect Early Vein Graft Patency in the Rat Femoral Artery Model

2018 ◽  
Vol 35 (04) ◽  
pp. 299-305
Author(s):  
Amro Harb ◽  
Maxwell Levi ◽  
Akio Kozato ◽  
Yelena Akelina ◽  
Robert Strauch
Keyword(s):  
Vein Graft ◽  
Graft Failure ◽  
Blood Flow Rate ◽  
Graft Patency ◽  
Sprague Dawley ◽  
Rat Models ◽  
Vein Grafts ◽  
Sprague Dawley Rats ◽  
Training Courses ◽  
Vein Graft Failure

Background Torsion of vein grafts is a commonly cited reason for graft failure in clinical setting. Many microsurgery training courses have incorporated vein graft procedures in their curricula, and vein graft torsion is a common technical error made by the surgeons in these courses. To improve our understanding of the clinical reproducibility of practicing vein graft procedures in microsurgery training courses, this study aims to determine if torsion can lead to early vein graft failure in nonsurvival surgery rat models. Methods Sprague-Dawley rats were divided into five cohorts with five rats per cohort for a total of 25 rats. Cohorts were labeled based on degree of vein graft torsion (0, 45, 90, 135, and 180 degrees). Torsion was created in the vein grafts at the distal arterial end by mismatching sutures placed between the proximal end of the vein graft and the distal arterial end. Vein graft patency was then verified 2 and 24 hours postoperation. Results All vein grafts were patent 2 and 24 hours postoperation. At 2 hours, the average blood flow rate measurements for 0, 45, 90, 135, and 180 degrees of torsion were 0.37 ± 0.02, 0.38 ± 0.04, 0.34 ± 0.01, 0.33 ± 0.01, and 0.29 ± 0.02 mL/min, respectively. At 24 hours, they were 0.94 ± 0.07, 1.03 ± 0.15, 1.26 ± 0.22, 1.41 ± 0.11, and 0.89 ± 0.15 mL/min, respectively. Conclusion Torsion of up to 180 degrees does not affect early vein graft patency in rat models. To improve the clinical reproducibility of practicing vein graft procedures in rat models, we suggest that microsurgery instructors assess vein graft torsion prior to clamp release, as vessel torsion does not seem to affect graft patency once the clamps are removed.

Gene Therapy for Vein Graft Failure Using Tissue Inhibitors of Metalloproteinases

1999 ◽  
Vol 97 (s41) ◽  
pp. 15P-15P
Author(s):  
SJ George ◽  
AH Baker ◽  
GD Angelini ◽  
AC Newby
Keyword(s):  
Gene Therapy ◽  
Vein Graft ◽  
Graft Failure ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Tissue Inhibitors ◽  
Vein Graft Failure

About the Impact of Extracardiac Vascular Disease on Vein Graft Failure

2014 ◽  
Vol 98 (5) ◽  
pp. 1889-1890 ◽  
Author(s):  
Ismail Yurekli ◽  
Habib Cakir ◽  
Yuksel Besir ◽  
Orhan Gokalp
Keyword(s):  
Vascular Disease ◽  
Vein Graft ◽  
Graft Failure ◽  
The Impact ◽  
Vein Graft Failure

Abstract 293: Clinical Predictors of Endothelial Function in Human Saphenous Vein

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Michael J Osgood ◽  
Kyle Hocking ◽  
Eric S Wise ◽  
Kevin W Sexton ◽  
Padmini Komalavilas ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Saphenous Vein ◽  
Intimal Hyperplasia ◽  
Vein Graft ◽  
Graft Failure ◽  
Univariate Analysis ◽  
Clinical Predictors ◽  
Human Saphenous Vein ◽  
Graft Harvest ◽  
Vein Graft Failure

BACKGROUND: Human saphenous vein (HSV) remains the most widely utilized conduit for vascular bypass procedures. Outcomes remain limited by vein graft failure and intimal hyperplasia. Endothelial function is considered an important determinant of vein graft failure. We have observed significant variability in endothelial function in freshly isolated HSV samples. We therefore evaluated clinical predictors of endothelial function in HSV. Methods: We obtained freshly isolated HSV samples from the operating room immediately following harvest from patients undergoing coronary artery bypass procedures from Vanderbilt University Hospital and the Nashville VA Hospital. We obtained HSV samples prior to any intraoperative manipulations. HSV viability, smooth muscle function, and endothelial-dependent relaxation (EDR) were measured in a muscle bath. We collected the following clinical and demographic information: age, height, weight, gender, ethnicity, medical comorbidities, laboratory values (creatinine, HbA1c, lipids), ejection fraction, preoperative medication regimen, and method of vein graft harvest. We performed a univariate and multivariate analysis of predictors of endothelial function in HSV. Results: HSV samples were obtained from 149 patients. HSV EDR varied from -11% to 63%. Open harvest was employed for 39 HSV samples, compared with endoscopic harvest in 110 HSV samples. On univariate analysis, only open harvest was a statistically significant predictor of endothelial function (p=0.02): mean HSV EDR was 21.5% in HSV samples harvested open, compared with 15.4% in HSV harvested with an endoscopic technique. HSV EDR was also improved with preoperative aspirin use: mean HSV EDR was 18% in patients with preoperative aspirin use compared with 11.6% in patients who were not administered preoperative aspirin in a multivariate model when controlling for method of vein graft harvest (p=0.05). Conclusions: Endoscopic vein graft harvest is associated with endothelial dysfunction in HSV, while preoperative aspirin use is associated with improved endothelial function. Further work will be necessary to determine whether these factors are associated with development of intimal hyperplasia and vein graft failure.

Abstract 2056: Blockade of PDGF Receptor Tyrosine Kinase by Ex Vivo Nano-DDS of Imatinib Mesylate into the Vein Suppresses Vein Graft Neointima Formation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Kimura ◽  
Kensuke Egahira ◽  
Hiroyuki Tsujimoto ◽  
Kaori Hara ◽  
Yoshiaki Kawashima ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Vein Graft ◽  
Graft Failure ◽  
Therapeutic Strategy ◽  
Jugular Vein ◽  
Ex Vivo ◽  
Pdgf Receptor ◽  
Neointima Formation ◽  
Vein Graft Failure

Background: Clinical outcome of surgical revascularization using autologous vein graft is limited by vein graft failure due to neointima formation. Platelet-derived growth factor (PDGF), expressed by vascular smooth muscle cells (VSMCs), plays a central role in the pathogenesis of vein graft failure. Therefore, optimal nanotechnology-based drug delivery system (Nano-DDS) of PDGF receptor tyrosine kinase (TK) inhibitor, imatinib mesylate (STI571), can be an innovative therapeutic strategy for clinical application. We have developed such Nano-DDS using bioabsorbable PLGA nanoparticles (NP) for local ex vivo delivery. Hypothesis: Blockade of PDGF receptor TK by Nano-DDS of imatinib suppresses vein graft neointima formation. Methods and Results: [studies in human VSMCs in vitro] Addition of fluorescence (FITC)-encapsulated NP resulted in rapid and stable uptake by 99 % of cells. The Nano-DDS of imatinib prevented PDGF-induced phosphorylation of PDGF receptor TK, and thus normalized the PDGF-induced proliferation. [ ex vivo studies] Incubation of excised rabbit jugular vein and human saphenous vein ex vivo in FITC-encapsulated NP for 30 min resulted in highly efficient intracellular delivery rate (> 90 % cells) into cells of the venous wall. [ in vivo studies in rabbits] The excised jugular vein was treated ex vivo with PBS, imatinib only (100 mM), FITC NP only, or imatinib NP (100 mM) (n=5– 6, each) for 30 min, and then interposed into the carotid artery position of hypercholesterolemic rabbits. Seven and 28 days after ex vivo FITC NP treatment, FITC-positive cells were detected in many cells in the neointima and media (cellular uptake rate: 60 –70 %). Significant neointima was formed 28 days after grafting in PBS group, which was suppressed in imatinib NP group, but not in FITC NP only or imatinib only groups. Imatinib NP also inhibited the appearance of proliferating PCNA-positive cells and increased phosphorylation of PDGF receptor TK, but did not affect monocyte infiltration or endothelial regeneration process. Conclusions: Nano-DDS of imatinib into the excised vein ex vivo was feasible and suppressed vein graft neointima formation in rabbits. Nano-DDS of imatinib may be a clinically promising therapeutic strategy for prevention of vein graft failure.

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