Arwen L Hunter

St. Paul's Hospital, Saskatoon, Saskatchewan, Canada

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Publications (8)24.09 Total impact

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    ABSTRACT: Peritransplant ischemia and reperfusion (I/R) injury contributes to posttransplant vascular dysfunction and cardiac allograft vasculopathy (CAV). We have previously shown that cytochrome p450 (CYP) 2C inhibition significantly reduces I/R-induced myocardial infarction and postischemic vascular dysfunction. In the latter study, pretreatment with sulfaphenazole (SP), a specific inhibitor of CYP 2C, restored postischemic NO-mediated, endothelium-dependent vasodilation and reduced vascular superoxide production. Given the association between I/R injury, early vascular dysfunction and CAV, we hypothesized that CYP 2C may also contribute to the onset of CAV. Lewis-to-Fisher rat heterotopic heart transplants were performed. Donors and recipients were treated with 5 mg/kg SP or vehicle control 1 h prior to surgery. SP did not affect posttransplant morbidity, mortality or weight gain. Coronary blood vessels from rats treated with SP exhibited significantly reduced luminal narrowing and demonstrated a corresponding decrease in smooth muscle cell (SMC) proliferation compared to controls. SP did not reduce diffuse, focal, epicardial, endocardial or perivascular immune infiltration nor did it significantly alter TUNEL positivity in myocardial, endothelial or SMC populations. In conclusion, CYP 2C contributes to SMC proliferation CAV without affecting general immune infiltration.
    American Journal of Transplantation 07/2008; 8(8):1631-8. · 6.19 Impact Factor
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    ABSTRACT: Vascular dysfunction is linked with increased free radical generation and is a major contributor to the high mortality rates observed in diabetes. Several probable sources of free radical generation have been suggested in diabetes, including cytochrome P450 (CYP) monooxygenase-dependent pathways. CYP-mediated superoxide production reduces nitric oxide (NO) bioavailability. In this study, we focus on the contribution of monooxygenase enzyme-generated reactive oxygen species in vascular dysfunction in an experimental model of diabetes mellitus type II. Diabetic male mice (db/db strain) and their age-matched controls received daily intraperitoneal injections of either the CYP 2C inhibitor sulfaphenazole (5.13 mg/kg) or saline (vehicle control) for 8 weeks. Although sulfaphenazole did not change endothelium-dependent vasodilation in control mice, it restored endothelium-mediated relaxation in db/db mice. We report for the first time that CYP 2C inhibition reduces oxidative stress (measured as plasma levels of 8-isoprostane), increases NO bioavailability (measured as NO(2)(-)) and restores endothelial function in db/db mice without affecting plasma glucose levels. Based on our findings, we speculate that inhibition of free radical generating CYP 450 monooxygenase enzymes restores endothelium-dependent vasodilation to acetylcholine. In addition, it reduces oxidative stress and increases NO bioavailability.
    Vascular Pharmacology 02/2008; 48(1):1-8. · 3.21 Impact Factor
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    ABSTRACT: Apoptosis repressor with caspase recruitment domain (ARC), an anti-apoptotic protein, is highly expressed in differentiated heart and skeletal muscle. Apoptosis and differentiation share numerous common pathways; therefore, we examined the impact of ARC on H9c2-myoblast differentiation. We demonstrate that ARC expression levels increase and stabilize upon differentiation. ARC-overexpression in pre-differentiated H9c2-cells suppresses differentiation; indicated by increased myotube formation, nuclear fusion and expression of the differentiation markers myogenin and troponin-T. ARC-overexpression inhibited myoblast differentiation associated caspase-3 activation, suggesting ARC inhibits myogenic differentiation through caspase inhibition. In summary, we show a novel role for ARC in the regulation of muscle differentiation.
    FEBS Letters 04/2007; 581(5):879-84. · 3.58 Impact Factor
  • Journal of Heart and Lung Transplantation - J HEART LUNG TRANSPLANT. 01/2007; 26(2).
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    ABSTRACT: Cytochrome p450 (CYP) inhibitors provide protection against myocardial infarction following both global and focal cardiac ischemia and reperfusion (I/R). We hypothesized that sulfaphenazole, an inhibitor of CYP2C6 and 9, also attenuates post-ischemic endothelial dysfunction by reducing CYP-mediated superoxide generation (which scavenges nitric oxide (NO)), thereby restoring NO bioavailability and vascular tone. Rat hearts were perfused in the Langendorff mode for 20 min in the presence, or absence, of sulfaphenazole and then subjected to 30 min global no-flow ischemia followed by 15 min reperfusion. Septal coronary resistance arteries were isolated and mounted on glass cannulae for measurements of luminal diameter. Preconstricted arteries were exposed to acetylcholine to elicit endothelium-dependent, NO-mediated vasodilation. Acetylcholine caused near maximal dilation in control tissues not subjected to I/R. Following I/R, endothelium-dependent vasodilation was reduced. Pretreatment with sulfaphenazole restored endothelial sensitivity to acetylcholine. Vasoresponsiveness to endothelium-independent vasodilators, sodium nitroprusside and isoproterenol, were also reduced following I/R. However, sensitivity to endothelium-independent vasodilators was not restored by pretreatment with sulfaphenazole. I/R-induced superoxide production was assessed by dihydroethidium staining of flash frozen hearts. Sulfaphenazole treatment significantly reduced superoxide production in arterial walls following I/R injury. We conclude that sulfaphenazole restores post-ischemic endothelium-dependent, NO-mediated vasodilation by reducing superoxide production, suggesting that CYP2C9 plays a key role in post-ischemic vascular dysfunction.
    Vascular Pharmacology 11/2005; 43(4):213-9. · 3.21 Impact Factor
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    ABSTRACT: The past decade has seen a surge in research devoted to understanding the role of cell death in the pathogenesis of various forms of cardiovascular disease. In particular, apoptosis has received much attention owing to the tightly regulated biochemical nature of this form of cell death and the realization of potential therapeutic opportunities. The current chapter describes a few of the more widely used protocols for detecting and quantifying apoptosis in cardiovascular tissues. Specifically, this chapter describes terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining for DNA fragmentation, Hoechst staining for chromatin condensation, annexin V labeling of phosphatidylserine externalization, and Western blot and immunoflorescence detection of caspase cleavage and activation, respectively.
    Methods in molecular medicine 02/2005; 112:277-89.
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    ABSTRACT: The cytochrome p450 (CYP) superfamily is responsible for the oxidation, peroxidation, and (or) reduction of vitamins, steroids, xenobiotics, and the majority of cardiovascular drugs in an oxygen- and NADPH-dependent manner. Although hepatic CYP have been studied extensively, the role of CYP in cardiovascular physiology and disease is poorly understood. Increasing evidence suggests that these enzymes play an important role in the pathogenesis of a number of cardiovascular diseases. The current review summarizes the understanding as to the role that dysregulated CYP expression and (or) activity may play in the onset and progression of cardiovascular disease.
    Canadian Journal of Physiology and Pharmacology 01/2005; 82(12):1053-60. · 1.56 Impact Factor
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    ABSTRACT: T cell-induced cytotoxicity, of which granzyme B is a key mediator, is believed to contribute to the pathogenesis of inflammatory vascular diseases. In this report, we investigate the mechanism of granzyme B-induced smooth muscle cell (SMC) death. The addition of purified granzyme B alone to cultured SMCs caused a significant reduction in cell viability. Chromatin condensation, phosphatidylserine externalization, and membrane blebbing were observed, indicating that the mechanism of granzyme B-induced SMC death was through apoptosis. Activated splenocytes from perforin-knockout mice induced SMC death through a granzyme B-mediated pathway. Inhibition of the proteolytic activities of caspases and granzyme B prevented granzyme B-induced SMC death, whereas attenuation of granzyme B internalization with mannose-6-phosphate (M6P) did not. Further, granzyme B induced the cleavage of several SMC extracellular proteins, including fibronectin, and reduced focal adhesion kinase phosphorylation. These results indicate that granzyme B can induce apoptosis of SMCs in the absence of perforin by cleaving extracellular proteins, such as fibronectin.
    Arteriosclerosis Thrombosis and Vascular Biology 01/2005; 24(12):2245-50. · 6.34 Impact Factor