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Article ; Online: Endoluminal Atherosclerotic Plaque Debulking Using Enzymatic and Ultrasonic Energy.

Wang, Zheng / Mansukhani, Neel A / Emond, Zachary M / Varu, Vinit N / Chen, Amy / Morgan, Courtney E / Vercammen, Janet M / Kibbe, Melina R

The Journal of surgical research

2018 Volume 233, Page(s) 335–344

Abstract: Background: Current procedures to treat severe atherosclerosis are traumatic to the arterial wall and often result in restenosis due to neointimal hyperplasia. We developed a novel therapy using a specially designed double occlusion balloon catheter, ... ...

Abstract	Background: Current procedures to treat severe atherosclerosis are traumatic to the arterial wall and often result in restenosis due to neointimal hyperplasia. We developed a novel therapy using a specially designed double occlusion balloon catheter, ultrasonic wire, and enzymatic digestion solution to atraumatically debulk atherosclerotic plaques. Materials and methods: A combination of different enzymes, chemicals, and treatment conditions were evaluated for its effect at reducing atherosclerotic plaque harvested from human carotid artery endarterectomies ex vivo. The optimized digestion solution was examined in harvested intact human superficial femoral arteries in situ. A conventional Yorkshire/Landrace and a genetically modified Yucatan minipig homozygous for a nonfunctional LDLR mutation were used to evaluate the endovascular therapy in nonatherosclerotic and atherosclerotic environments in vivo. Results: Ex vivo, the technology successfully digested human carotid artery plaques by 75%. In situ, the therapy successfully reduced plaque area in harvested superficial femoral arteries by 46%. In vivo, the endovascular therapy was technically feasible and demonstrated initial safety with no thrombosis, dissection, or aneurysmal dilatation in a nonatherosclerotic porcine model. In an atherosclerotic porcine model, the therapy demonstrated initial efficacy by successfully reducing atherosclerotic plaque while preserving the arterial wall with an intact internal elastic lamina. Conclusions: Using human plaque, human artery, and a normal and atherosclerotic pig model, we demonstrated that delivery of our therapy to the vasculature is technically feasible, appears safe, and shows initial efficacy. Our percutaneous plaque debulking method is a unique and promising therapy for the treatment of atherosclerosis and warrants further study.
MeSH term(s)	Angioplasty, Balloon/instrumentation ; Angioplasty, Balloon/methods ; Animals ; Animals, Genetically Modified ; Atherosclerosis/etiology ; Atherosclerosis/pathology ; Atherosclerosis/therapy ; Carotid Arteries/pathology ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Feasibility Studies ; Femoral Artery/pathology ; Humans ; Hydrolases/administration & dosage ; Iliac Artery/pathology ; Male ; Plaque, Atherosclerotic/pathology ; Plaque, Atherosclerotic/therapy ; Receptors, LDL/genetics ; Swine ; Swine, Miniature ; Treatment Outcome ; Ultrasonic Therapy/methods
Chemical Substances	Receptors, LDL ; Hydrolases (EC 3.-)
Language	English
Publishing date	2018-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80170-7
ISSN	1095-8673 ; 0022-4804
ISSN (online)	1095-8673
ISSN	0022-4804
DOI	10.1016/j.jss.2018.08.012
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Zs.A 178: Show issues

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Article ; Online: Reentry device aided endovascular aneurysm repair in patients with abdominal aortic aneurysm and unilateral iliac artery occlusion.

Varu, Vinit N / Lee, George K / Chang, Shu / Lee, Jason T

Annals of vascular surgery

2014 Volume 28, Issue 7, Page(s) 1800.e1–7

Abstract: Background: We report 2 cases of patients undergoing endovascular aneurysm repair (EVAR) using reentry devices to recanalize unilateral iliac artery occlusions and complete a bifurcated endovascular repair.: Methods: Patient 1 is a 70-year-old male ... ...

Abstract	Background: We report 2 cases of patients undergoing endovascular aneurysm repair (EVAR) using reentry devices to recanalize unilateral iliac artery occlusions and complete a bifurcated endovascular repair. Methods: Patient 1 is a 70-year-old male with an enlarging 6.5-cm abdominal aortic aneurysm (AAA) and disabling left leg claudication with L external iliac occlusion with patent common and internal iliac arteries. Patient 2 is a 67-year-old male with an asymptomatic 4.0-cm AAA and L iliac chronic total occlusion (CTO) and disabling claudication. Both patients were poor operative candidates for open repair. Results: Both patients underwent elective percutaneous EVAR along with left iliac artery revascularization. Initial angiography in both cases showed a blind ending of the left common iliac artery. Retrograde subintimal dissection through the occluded iliac segment was attempted but in both cases the wire was unable to traverse back into the true aortic lumen. Using either the Outback LTD or Pioneer reentry catheter, direct visualization of the true aortic lumen was obtained to re-enter the true lumen. The subintimal iliac tract was then predilated to facilitate routine EVAR in both cases. Both patients were discharged the following day and 1-year and 6-month follow-up imaging revealed aneurysm exclusion, no endoleak, and patent bilateral common iliac arteries with resolution of claudication symptoms and normal ankle-brachial indexes. The previously patent internal iliac artery was preserved. Conclusions: While not always technically possible, reentry device aided EVAR is safe, feasible, and durable in the mid-term and avoids the morbidity and mortality related to aortouniiliac/femoral-femoral bypass and open repair. This technique should be considered in patients with iliac artery CTO and concurrent AAA to allow total endovascular repair.
MeSH term(s)	Aged ; Aortic Aneurysm, Abdominal/complications ; Aortic Aneurysm, Abdominal/diagnosis ; Aortic Aneurysm, Abdominal/surgery ; Diagnostic Imaging ; Endovascular Procedures/instrumentation ; Humans ; Iliac Aneurysm/complications ; Iliac Aneurysm/diagnosis ; Iliac Aneurysm/surgery ; Intermittent Claudication/diagnosis ; Intermittent Claudication/etiology ; Intermittent Claudication/surgery ; Male
Language	English
Publishing date	2014-10
Publishing country	Netherlands
Document type	Case Reports ; Journal Article
ZDB-ID	1027366-9
ISSN	1615-5947 ; 0890-5096
ISSN (online)	1615-5947
ISSN	0890-5096
DOI	10.1016/j.avsg.2014.05.008
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Zs.A 2882: Show issues

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Article ; Online: Renal function changes after snorkel/chimney repair of juxtarenal aneurysms.

Lee, Jason T / Varu, Vinit N / Tran, Kenneth / Dalman, Ronald L

Journal of vascular surgery

2014 Volume 60, Issue 3, Page(s) 563–570

Abstract: Objective: The snorkel approach for endovascular aneurysm repair (EVAR) has been found to be a safe and viable alternative to open repair for juxtarenal abdominal aortic aneurysms with good short-term outcomes. Concerns about long-term durability and ... ...

Abstract	Objective: The snorkel approach for endovascular aneurysm repair (EVAR) has been found to be a safe and viable alternative to open repair for juxtarenal abdominal aortic aneurysms with good short-term outcomes. Concerns about long-term durability and renal branch patency with this technique have been raised with the increasing availability of fenestrated devices. We sought to evaluate renal function changes in patients undergoing "snorkel" EVAR (sn-EVAR). Methods: Patients who underwent sn-EVAR from 2009 to 2012 were included in this analysis. Creatinine values were obtained throughout the patient's preoperative, perioperative, and postoperative course. Glomerular filtration rate (GFR) was estimated by the simplified Modification of Diet in Renal Disease formula. Acute renal dysfunction was analyzed according to the RIFLE (Risk, Injury, Failure, Loss, End stage) criteria, whereas chronic renal dysfunction was stratified by the chronic kidney disease staging system. Results: Forty-three consecutive patients underwent sn-EVAR (31 double renal, 12 single renal) for juxtarenal aortic aneurysms. Mean follow-up time was 21 months. Mean aneurysm size was 6.6 cm (range, 5.1-10.5 cm) with anatomy not suitable for treatment with standard EVAR (mean neck length, 1.6 mm); 74 renal snorkel stents were placed in these patients with a 2-year primary patency of 95%. On average, the cohort at baseline was stratified as having moderate renal dysfunction. Mean baseline, maximum postoperative, and latest follow-up creatinine concentrations were 1.20, 1.49, and 1.43, respectively (P = .004). Mean baseline, maximum postoperative, and latest follow-up GFRs were 57.4, 47.8, and 49.2, respectively (P = .014). With use of RIFLE criteria, 14 patients (32.6%) experienced some form of acute kidney injury, although 10 of these patients (23.3%) were classified as mild (25%-50% decline in GFR). On analysis without the RIFLE criteria, 21.4% of patients had postoperative creatinine concentration >1.5 mg/dL, 28.6% had postoperative creatinine concentration increase >30%, and 28.6% had postoperative GFR decline >30%. For the entire study cohort at latest follow-up, 51% experienced no decline of chronic renal dysfunction and 8.1% had improvement in renal function. Renal function declined by one stage in 35.2% of the cohort and by two stages in 5.4%. On analysis without chronic kidney disease staging, 24.3% of patients had latest follow-up creatinine concentration >1.5 mg/dL, 29.7% had latest follow-up creatinine concentration increase >30%, and 24.3% had latest follow-up GFR decline >30%. Mean survival time from significant renal decline was 23.4 months. Conclusions: sn-EVAR continues to demonstrate a high rate of technical success and results in only mild rates of acute and midterm renal function decline according to a number of established definitions for renal dysfunction. Continued monitoring of renal function, renal stent behavior, and abdominal aortic aneurysm sac changes remains critically important in the long-term management of patients undergoing sn-EVAR, particularly given the high comorbidities associated with juxtarenal aortic aneurysms.
MeSH term(s)	Acute Kidney Injury/blood ; Acute Kidney Injury/etiology ; Acute Kidney Injury/physiopathology ; Aged ; Aged, 80 and over ; Aortic Aneurysm, Abdominal/diagnosis ; Aortic Aneurysm, Abdominal/physiopathology ; Aortic Aneurysm, Abdominal/surgery ; Biomarkers/blood ; Blood Vessel Prosthesis ; Blood Vessel Prosthesis Implantation/instrumentation ; Blood Vessel Prosthesis Implantation/methods ; Creatinine/blood ; Disease Progression ; Endovascular Procedures/instrumentation ; Endovascular Procedures/methods ; Female ; Glomerular Filtration Rate ; Humans ; Kidney/physiopathology ; Male ; Middle Aged ; Prosthesis Design ; Registries ; Renal Insufficiency, Chronic/blood ; Renal Insufficiency, Chronic/etiology ; Renal Insufficiency, Chronic/physiopathology ; Risk Factors ; Stents ; Time Factors ; Treatment Outcome
Chemical Substances	Biomarkers ; Creatinine (AYI8EX34EU)
Language	English
Publishing date	2014-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	605700-7
ISSN	1097-6809 ; 0741-5214
ISSN (online)	1097-6809
ISSN	0741-5214
DOI	10.1016/j.jvs.2014.03.239
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Zs.A 1933: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Anatomic suitability of aortoiliac aneurysms for next generation branched systems.

Pearce, Benjamin J / Varu, Vinit N / Glocker, Roan / Novak, Zdenek / Jordan, William D / Lee, Jason T

Annals of vascular surgery

2015 Volume 29, Issue 1, Page(s) 69–75

Abstract: Background: Preservation of internal iliac flow is an important consideration to prevent ischemic complications during endovascular aneurysm repair. We sought to determine the suitability of aortoiliac aneurysms for off-the-shelf iliac branched systems ... ...

Abstract	Background: Preservation of internal iliac flow is an important consideration to prevent ischemic complications during endovascular aneurysm repair. We sought to determine the suitability of aortoiliac aneurysms for off-the-shelf iliac branched systems currently in clinical trial. Methods: Patients undergoing abdominal aortic aneurysm repair from 2004 to 2013 at 2 institutions were reviewed. Centerline diameters and lengths of aortoiliac morphology were measured using three-dimensional workstations and compared with inclusion/exclusion criteria for both Cook and Gore iliac branch devices. Results: Of the nearly 2,400 aneurysm repairs performed during the study period, 99 patients had common iliac aneurysms suitable for imaging review. Eighteen of the 99 (18.2%) patients and 25/99 (25.3%) patients fit the inclusion criteria and would have been able to be treated using the Cook and Gore iliac branch devices, respectively. The most common reason for exclusion from Cook was internal iliac diameter of <6 or >9 mm (68/99, 68.7%). The most common reason for exclusion from Gore was proximal common iliac diameter of <17 mm (39/99, 39.4%) and inadequate internal iliac artery diameter of <6.5 or >13.5 mm (37/99, 37.3%). Comparing the included patients across both devices, a total of 35/99 (35.4%) of patients would be eligible for the treatment of aortoiliac aneurysms based on anatomic criteria. Conclusions: Only 35% of the aneurysm repairs involving common iliac arteries would have been candidates for the 2 iliac branch devices currently in trial based on anatomic criteria. The major common reason for exclusion is the internal iliac landing zone for both devices. Design modifications for future generation iliac branch technology should focus on diameter accommodations for the hypogastric branch stent and proximal and distal sizes of the iliac branch components. Familiarity with alternate branch preserving techniques is still needed in the majority of cases.
MeSH term(s)	Alabama ; Aortic Aneurysm, Abdominal/diagnosis ; Aortic Aneurysm, Abdominal/surgery ; Aortography/methods ; Blood Vessel Prosthesis ; Blood Vessel Prosthesis Implantation/adverse effects ; Blood Vessel Prosthesis Implantation/instrumentation ; California ; Endovascular Procedures/adverse effects ; Endovascular Procedures/instrumentation ; Humans ; Iliac Aneurysm/diagnosis ; Iliac Aneurysm/surgery ; Prosthesis Design ; Retrospective Studies ; Time Factors ; Tomography, X-Ray Computed ; Treatment Outcome
Language	English
Publishing date	2015-01
Publishing country	Netherlands
Document type	Journal Article ; Multicenter Study
ZDB-ID	1027366-9
ISSN	1615-5947 ; 0890-5096
ISSN (online)	1615-5947
ISSN	0890-5096
DOI	10.1016/j.avsg.2014.08.003
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Zs.A 2882: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Critical limb ischemia.

Varu, Vinit N / Hogg, Melissa E / Kibbe, Melina R

Journal of vascular surgery

2010 Volume 51, Issue 1, Page(s) 230–241

Abstract: Critical limb ischemia (CLI) continues to be a significantly morbid disease process for the aging population. Rigid guidelines for the management of patients with CLI are inappropriate due to the complexities that are involved in optimally treating these ...

Abstract	Critical limb ischemia (CLI) continues to be a significantly morbid disease process for the aging population. Rigid guidelines for the management of patients with CLI are inappropriate due to the complexities that are involved in optimally treating these patients. A thin line exists in the decision process between medical management vs surgical management by revascularization or amputation, and the perception of "success" in this patient population is evolving. This review explores these issues and examines the challenges the treating physician will face when managing the care of patients with CLI. The epidemiology and natural history of CLI is discussed, along with the pathophysiology of the disease process. A review of the literature in regards to the different treatment modalities is presented to help the physician optimize therapy for patients with CLI. New scoring systems to help predict outcomes in patients with CLI undergoing revascularization or amputation are discussed, and an overview of the current status of patient-oriented outcomes is provided. Finally, we briefly examine emerging therapies for the treatment of CLI and provide an algorithm to help guide the practicing physician on how to approach the critically ischemic limb with regard to the complicated issues surrounding these patients.
MeSH term(s)	Algorithms ; Amputation ; Cardiovascular Agents/adverse effects ; Cardiovascular Agents/therapeutic use ; Clinical Protocols ; Critical Illness ; Disease Progression ; Humans ; Ischemia/diagnosis ; Ischemia/epidemiology ; Ischemia/physiopathology ; Ischemia/therapy ; Limb Salvage ; Lower Extremity/blood supply ; Patient Selection ; Practice Guidelines as Topic ; Predictive Value of Tests ; Reoperation ; Risk Assessment ; Risk Factors ; Severity of Illness Index ; Time Factors ; Treatment Outcome ; Vascular Patency ; Vascular Surgical Procedures/adverse effects
Chemical Substances	Cardiovascular Agents
Language	English
Publishing date	2010-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	605700-7
ISSN	1097-6809 ; 0741-5214
ISSN (online)	1097-6809
ISSN	0741-5214
DOI	10.1016/j.jvs.2009.08.073
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Zs.A 1933: Show issues

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Article: Basic science review: nitric oxide--releasing prosthetic materials.

Varu, Vinit N / Tsihlis, Nick D / Kibbe, Melina R

Vascular and endovascular surgery

2009 Volume 43, Issue 2, Page(s) 121–131

Abstract: Prosthetic devices that come into contact with blood ultimately fail secondary to thrombus formation. This limits the utility of a variety of materials used to surgically treat cardiovascular disease, including vascular grafts and stents, as well as ... ...

Abstract	Prosthetic devices that come into contact with blood ultimately fail secondary to thrombus formation. This limits the utility of a variety of materials used to surgically treat cardiovascular disease, including vascular grafts and stents, as well as sensors and catheters placed within the circulatory system. Moreover, systemic anticoagulation that is used to prevent malfunction of these devices has potential for serious complications. It is known that nitric oxide (NO) produced via the endothelium imparts thromboresistant properties to native blood vessels. Thus, if NO were delivered locally to the site of the prosthetic material, it has the potential to halt thrombus formation while limiting life-threatening side effects. This review serves to examine the variety of NO-releasing materials that have been created with the two different classes of NO donors, the diazeniumdiolates and S-nitrosothiols, and the clinical applications of these prosthetics for potential future use.
MeSH term(s)	Animals ; Anticoagulants/therapeutic use ; Azo Compounds/therapeutic use ; Blood Coagulation/drug effects ; Blood Vessel Prosthesis ; Blood Vessel Prosthesis Implantation/adverse effects ; Blood Vessel Prosthesis Implantation/instrumentation ; Coated Materials, Biocompatible ; Drug Therapy, Combination ; Drug-Eluting Stents ; Humans ; Nitric Oxide Donors/administration & dosage ; Nitric Oxide Donors/therapeutic use ; Prosthesis Design ; Prosthesis Failure ; S-Nitrosothiols/therapeutic use ; Thrombosis/blood ; Thrombosis/etiology ; Thrombosis/prevention & control
Chemical Substances	Anticoagulants ; Azo Compounds ; Coated Materials, Biocompatible ; Nitric Oxide Donors ; S-Nitrosothiols ; diazeniumdiolate
Language	English
Publishing date	2009-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2076272-0
ISSN	1938-9116 ; 1538-5744
ISSN (online)	1938-9116
ISSN	1538-5744
DOI	10.1177/1538574408322752
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Zs.A 622: Show issues

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Article ; Online: Nitric oxide affects UbcH10 levels differently in type 1 and type 2 diabetic rats.

Rodriguez, Monica P / Tsihlis, Nick D / Emond, Zachary M / Wang, Zheng / Varu, Vinit N / Jiang, Qun / Vercammen, Janet M / Kibbe, Melina R

The Journal of surgical research

2015 Volume 196, Issue 1, Page(s) 180–189

Abstract: Background: Nitric oxide (NO) more effectively inhibits neointimal hyperplasia in type 2 diabetic versus nondiabetic and type 1 diabetic rodents. NO also decreases the ubiquitin-conjugating enzyme UbcH10, which is critical to cell-cycle regulation. This ...

Abstract	Background: Nitric oxide (NO) more effectively inhibits neointimal hyperplasia in type 2 diabetic versus nondiabetic and type 1 diabetic rodents. NO also decreases the ubiquitin-conjugating enzyme UbcH10, which is critical to cell-cycle regulation. This study seeks to determine whether UbcH10 levels in the vasculature of diabetic animal models account for the differential efficacy of NO at inhibiting neointimal hyperplasia. Materials and methods: Vascular smooth muscle cells (VSMCs) harvested from nondiabetic lean Zucker (LZ) and type 2 diabetic Zucker diabetic fatty (ZDF) rats were exposed to high glucose (25 mM) and high insulin (24 nM) conditions to mimic the diabetic environment in vitro. LZ, streptozotocin-injected LZ (STZ, type 1 diabetic), and ZDF rats underwent carotid artery balloon injury (±10 mg PROLI/NO), and vessels were harvested at 3 and 14 d. UbcH10 was assessed by Western blotting and immunofluorescent staining. Results: NO more effectively reduced UbcH10 levels in LZ versus ZDF VSMCs; however, addition of insulin and glucose dramatically potentiated the inhibitory effect of NO on UbcH10 in ZDF VSMCs. Three days after balloon injury, Western blotting showed NO decreased free UbcH10 and increased polyubiquitinated UbcH10 levels by 35% in both STZ and ZDF animals. Fourteen days after injury, immunofluorescent staining showed increased UbcH10 levels throughout the arterial wall in all animal models. NO decreased UbcH10 levels in LZ and STZ rats but not in ZDF. Conclusions: These data suggest a disconnect between UbcH10 levels and neointimal hyperplasia formation in type 2 diabetic models and contribute valuable insight regarding differential efficacy of NO in these models.
MeSH term(s)	Animals ; Blood Glucose/analysis ; Cells, Cultured ; Diabetes Mellitus, Experimental/blood ; Diabetes Mellitus, Experimental/pathology ; Diabetes Mellitus, Type 1/blood ; Diabetes Mellitus, Type 1/pathology ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/pathology ; Hyperplasia ; Male ; Muscle, Smooth, Vascular/chemistry ; Neointima/pathology ; Nitric Oxide/pharmacology ; Rats ; Rats, Zucker ; Streptozocin ; Ubiquitin-Conjugating Enzymes/blood ; Ubiquitination
Chemical Substances	Blood Glucose ; Nitric Oxide (31C4KY9ESH) ; Streptozocin (5W494URQ81) ; Ube2c protein, mouse (EC 2.3.2.23) ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23)
Language	English
Publishing date	2015-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80170-7
ISSN	1095-8673 ; 0022-4804
ISSN (online)	1095-8673
ISSN	0022-4804
DOI	10.1016/j.jss.2015.02.012
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Article ; Online: Nitric oxide differentially affects ERK and Akt in type 1 and type 2 diabetic rats.

Rodriguez, Monica P / Emond, Zachary M / Varu, Vinit N / Ahanchi, Sadaf S / Martinez, Janet / Kibbe, Melina R

The Journal of surgical research

2013 Volume 183, Issue 2, Page(s) 944–951

Abstract: ... NO (20 mg/kg) (n = 6/group).: Results: Three days following injury, all animal models exhibited ...

Abstract	Background: We have shown that nitric oxide (NO) is more effective at inhibiting neointimal hyperplasia in type 2 diabetic rats than in nondiabetic rats, but is not effective in type 1 diabetic rats. Insulin signaling is mediated by the ERK and Akt pathways, and thus we hypothesized that NO differentially affects ERK and Akt activity in type 1 versus type 2 diabetic rats. Materials and methods: To investigate this hypothesis, we induced type 2 diabetes in Zucker diabetic fatty (ZDF) rats by feeding them Purina 5008 chow. To induce type 1 diabetes, lean Zucker (LZ) rats were injected with streptozotocin (STZ; 60 mg/kg). The carotid artery injury model was performed. Groups included injury and injury + PROLI/NO (20 mg/kg) (n = 6/group). Results: Three days following injury, all animal models exhibited an increase in pERK levels. Whereas NO reduced pERK levels in LZ and STZ rats, NO had no effect on pERK levels in ZDF rats. Following a similar pattern, NO reduced pAkt levels in LZ and STZ rats but increased pAkt levels in ZDF rats. Fourteen days following injury, NO increased total pERK levels throughout the arterial wall in both the STZ and ZDF rats. These changes were greatest in the adventitia. Interestingly, whereas NO decreased total pAkt levels in LZ and STZ rats, NO increased pAkt levels in ZDF rats. Evaluation of the pERK:pAkt ratio revealed that NO increased this ratio in LZ and STZ rats but decreased the ratio in ZDF rats. Conclusions: We report that NO differentially affects the expression of pERK and pAkt in type 1 versus type 2 diabetic rats. Given that NO is more effective at inhibiting neointimal hyperplasia in type 2 diabetic animals, the pERK:pAkt ratio may be the best surrogate to predict efficacy.
MeSH term(s)	Animals ; Diabetes Mellitus, Experimental/chemically induced ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 1/pathology ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Disease Models, Animal ; Extracellular Signal-Regulated MAP Kinases/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Hyperplasia ; Male ; Neointima/pathology ; Nitric Oxide/pharmacology ; Proto-Oncogene Proteins c-akt/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Zucker ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Streptozocin/adverse effects
Chemical Substances	Nitric Oxide (31C4KY9ESH) ; Streptozocin (5W494URQ81) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24)
Language	English
Publishing date	2013-03-19
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80170-7
ISSN	1095-8673 ; 0022-4804
ISSN (online)	1095-8673
ISSN	0022-4804
DOI	10.1016/j.jss.2013.02.055
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Zs.A 178: Show issues

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Article ; Online: Effect of nitric oxide on neointimal hyperplasia based on sex and hormone status.

Hogg, Melissa E / Varu, Vinit N / Vavra, Ashley K / Popowich, Daniel A / Banerjee, Monisha N / Martinez, Janet / Jiang, Qun / Saavedra, Joseph E / Keefer, Larry K / Kibbe, Melina R

Free radical biology & medicine

2011 Volume 50, Issue 9, Page(s) 1065–1074

Abstract: Nitric oxide (NO)-based therapies decrease neointimal hyperplasia; however, studies have been performed only in male animal models. Thus, we sought to evaluate the effect of NO on vascular smooth muscle cells (VSMC) in vitro and neointimal hyperplasia in ...

Abstract	Nitric oxide (NO)-based therapies decrease neointimal hyperplasia; however, studies have been performed only in male animal models. Thus, we sought to evaluate the effect of NO on vascular smooth muscle cells (VSMC) in vitro and neointimal hyperplasia in vivo based on sex and hormone status. In hormone-replete medium, male VSMC proliferated at greater rates than female VSMC. In hormone-depleted medium, female VSMC proliferated at greater rates than male VSMC. However, in both hormone environments, NO inhibited proliferation and migration to a greater extent in male compared to female VSMC. These findings correlated with greater G₀/G₁ cell cycle arrest and changes in cell cycle protein expression in male compared to female VSMC after exposure to NO. Next, the rat carotid artery injury model was used to assess the effect of NO on neointimal hyperplasia in vivo. Consistent with the in vitro data, NO was significantly more effective at inhibiting neointimal hyperplasia in hormonally intact males compared to females using weight-based dosing. An increased weight-based dose of NO in females was able to achieve efficacy equal to that in males. Surprisingly, NO was less effective at inhibiting neointimal hyperplasia in castrated animals of both sexes. In conclusion, these data suggest that NO inhibits neointimal hyperplasia more effectively in males compared to females and in hormonally intact compared to castrated rats, indicating that the effects of NO in the vasculature may be sex- and hormone-dependent.
MeSH term(s)	Animals ; Aorta/metabolism ; Aorta/pathology ; Azo Compounds/metabolism ; Azo Compounds/pharmacology ; Carotid Artery Injuries/metabolism ; Carotid Artery Injuries/pathology ; Castration ; Cell Culture Techniques ; Cell Cycle/drug effects ; Cell Cycle Proteins/analysis ; Cell Cycle Proteins/biosynthesis ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Female ; Hormones/analysis ; Hormones/biosynthesis ; Hyperplasia/drug therapy ; Hyperplasia/metabolism ; Hyperplasia/pathology ; Hyperplasia/prevention & control ; Male ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; Neointima/drug therapy ; Neointima/metabolism ; Neointima/pathology ; Neointima/prevention & control ; Nitric Oxide/pharmacology ; Nitric Oxide Donors/metabolism ; Nitric Oxide Donors/pharmacology ; Rats ; Rats, Sprague-Dawley ; Sex Factors
Chemical Substances	Azo Compounds ; Cell Cycle Proteins ; Hormones ; Nitric Oxide Donors ; diazeniumdiolate ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2011-01-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2011.01.016
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Insulin enhances the effect of nitric oxide at inhibiting neointimal hyperplasia in a rat model of type 1 diabetes.

Varu, Vinit N / Ahanchi, Sadie S / Hogg, Melissa E / Bhikhapurwala, Hussein A / Chen, Amy / Popowich, Daniel A / Vavra, Ashley K / Martinez, Janet / Jiang, Qun / Saavedra, Joseph E / Hrabie, Joseph A / Keefer, Larry K / Kibbe, Melina R

American journal of physiology. Heart and circulatory physiology

2010 Volume 299, Issue 3, Page(s) H772–9

Abstract: Diabetes confers greater restenosis from neointimal hyperplasia following vascular interventions. While localized administration of nitric oxide (NO) is known to inhibit neointimal hyperplasia, the effect of NO in type 1 diabetes is unknown. Thus the aim ...

Abstract	Diabetes confers greater restenosis from neointimal hyperplasia following vascular interventions. While localized administration of nitric oxide (NO) is known to inhibit neointimal hyperplasia, the effect of NO in type 1 diabetes is unknown. Thus the aim of this study was to determine the efficacy of NO following arterial injury, with and without exogenous insulin administration. Vascular smooth muscle cells (VSMC) from lean Zucker (LZ) rats were exposed to the NO donor, DETA/NO, following treatment with different glucose and/or insulin concentrations. DETA/NO inhibited VSMC proliferation in a concentration-dependent manner to a greater extent in VSMC exposed to normal-glucose vs. high-glucose environments, and even more effectively in normal-glucose/high-insulin and high-glucose/high-insulin environments. G(0)/G(1) cell cycle arrest and cell death were not responsible for the enhanced efficacy of NO in these environments. Next, type 1 diabetes was induced in LZ rats with streptozotocin. The rat carotid artery injury model was performed. Type 1 diabetic rats experienced no significant reduction in neointimal hyperplasia following arterial injury and treatment with the NO donor PROLI/NO. However, daily administration of insulin to type 1 diabetic rats restored the efficacy of NO at inhibiting neointimal hyperplasia (60% reduction, P < 0.05). In conclusion, these data demonstrate that NO is ineffective at inhibiting neointimal hyperplasia in an uncontrolled rat model of type 1 diabetes; however, insulin administration restores the efficacy of NO at inhibiting neointimal hyperplasia. Thus insulin may play a role in regulating the downstream beneficial effects of NO in the vasculature.
MeSH term(s)	Analysis of Variance ; Animals ; Aorta/drug effects ; Aorta/metabolism ; Aorta/pathology ; Carotid Arteries/drug effects ; Carotid Arteries/metabolism ; Carotid Arteries/pathology ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 1/pathology ; Drug Interactions ; Flow Cytometry ; Hyperplasia/metabolism ; Hyperplasia/pathology ; Insulin/metabolism ; Insulin/pharmacology ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/pathology ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/metabolism ; Myocytes, Smooth Muscle/pathology ; Nitric Oxide/metabolism ; Nitric Oxide/pharmacology ; Rats ; Tunica Intima/drug effects ; Tunica Intima/metabolism ; Tunica Intima/pathology
Chemical Substances	Insulin ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2010-06-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.01234.2009
Database	MEDical Literature Analysis and Retrieval System OnLINE

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