Vinit N Varu

Northwestern University, Evanston, IL, United States

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Publications (9)20.57 Total impact

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    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.
    Journal of Surgical Research 03/2013; · 2.02 Impact Factor
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    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.
    Free Radical Biology & Medicine 01/2011; 50(9):1065-74. · 5.27 Impact Factor
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    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.
    AJP Heart and Circulatory Physiology 09/2010; 299(3):H772-9. · 4.01 Impact Factor
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    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.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 01/2010; 51(1):230-41. · 3.52 Impact Factor
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    Journal of Vascular Surgery - J VASC SURG. 01/2010; 51(6).
  • Journal of Surgical Research - J SURG RES. 01/2009; 151(2):229-229.
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    ABSTRACT: Type II diabetes mellitus (DM) and metabolic syndrome are associated with accelerated restenosis following vascular interventions due to neointimal hyperplasia. The efficacy of nitric oxide (NO)-based therapies is unknown in these environments. Therefore, the aim of this study is to examine the efficacy of NO in preventing neointimal hyperplasia in animal models of type II DM and metabolic syndrome and examine possible mechanisms for differences in outcomes. Aortic vascular smooth muscle cells (VSMC) were harvested from rodent models of type II DM (Zucker diabetic fatty), metabolic syndrome (obese Zucker), and their genetic control (lean Zucker). Interestingly, NO inhibited proliferation and induced G0/G1 cell cycle arrest to the greatest extent in VSMC from rodent models of metabolic syndrome and type II DM compared with controls. This heightened efficacy was associated with increased expression of cyclin-dependent kinase inhibitor p21, but not p27. Using the rat carotid artery injury model to assess the efficacy of NO in vivo, we found that the NO donor PROLI/NO inhibited neointimal hyperplasia to the greatest extent in type II DM rodents, followed by metabolic syndrome, then controls. Increased neointimal hyperplasia correlated with increased reactive oxygen species (ROS) production, as demonstrated by dihydroethidium staining, and NO inhibited this increase most in metabolic syndrome and DM. In conclusion, NO was surprisingly a more effective inhibitor of neointimal hyperplasia following arterial injury in type II DM and metabolic syndrome vs. control. This heightened efficacy may be secondary to greater inhibition of VSMC proliferation through cell cycle arrest and regulation of ROS expression, in addition to other possible unidentified mechanisms that deserve further exploration.
    AJP Heart and Circulatory Physiology 11/2008; 295(6):H2388-98. · 4.01 Impact Factor
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    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.
    Vascular and Endovascular Surgery 10/2008; 43(2):121-31. · 0.88 Impact Factor
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    ABSTRACT: Atherosclerosis in the form of peripheral arterial disease results in significant morbidity and mortality. Surgical treatment options for peripheral arterial disease include angioplasty with and without stenting, endarterectomy, and bypass grafting. Unfortunately, all of these procedures injure the vascular endothelium, which impairs its ability to produce nitric oxide (NO) and ultimately leads to neointimal hyperplasia and restenosis. To improve on current patency rates after vascular procedures, investigators are engaged in research to improve the bioavailability of NO at the site of vascular injury in an attempt to reduce the risk of thrombosis and restenosis after successful revascularization. This article reviews some of the previous research that has aimed to improve NO bioavailability after vascular procedures whether through systemic or local delivery, as well as to describe some of the NO-releasing products that are currently undergoing study for use in clinical practice.
    Vascular 12/2007; 15(6):324-35. · 0.86 Impact Factor