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Apocynin Exerts Dose-Dependent Cardioprotective Effects by Attenuating Reactive Oxygen Species in Ischemia/Reperfusion

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Apocynin Exerts Dose-Dependent Cardioprotective Effects by Attenuating Reactive Oxygen Species in Ischemia/Reperfusion maco har log P y: r O la Chen et al., Cardiovasc Pharm Open Access 2016, 5:2 u p c e n s a A DOI: 10.4176/2329-6607.1000176 v c o c i e d r s a s Open Access C Cardiovascular Pharmacology: ISSN: 2329-6607 Research Article OpenOpen Access Access Apocynin Exerts Dose-Dependent Cardioprotective Effects by Attenuating Reactive Oxygen Species in Ischemia/Reperfusion Qian Chen, Woodworth Parker C, Issachar Devine, Regina Ondrasik, Tsion Habtamu, Kyle D Bartol, Brendan Casey, Harsh Patel, William Chau, Tarah Kuhn, Robert Barsotti and Lindon Young* Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, USA Abstract Ischemia/reperfusion results in cardiac contractile dysfunction and cell death partly due to increased reactive oxygen species and decreased endothelial-derived nitric oxide bioavailability. NADPH oxidase normally produces reactive oxygen species to facilitate cell signalling and differentiation; however, excessive release of such species following ischemia exacerbates cell death. Thus, administration of an NADPH oxidase inhibitor, apocynin, may preserve cardiac function and reduce infarct size following ischemia. Apocynin dose-dependently (40 μM, 400 μM and 1 mM) attenuated leukocyte superoxide release by 87 ± 7%. Apocynin was also given to isolated perfused hearts after ischemia, with infarct size decreasing to 39 ± 7% (40 μM), 28 ± 4% (400 μM; p < 0.01) and 29 ± 6% (1 mM; p < 0.01), versus the control’s 46 ± 2%. This decrease correlated with improved final post-reperfusion left ventricular end-diastolic pressure, which decreased from 60 ± 5% in control hearts to 56 ± 5% (40 µM), 43 ± 4% (400 μM; p < 0.01) and 48 ± 5% (1 mM; p < 0.05), compared to baseline. Functionally, apocynin (13.7 mg/kg, I.V.) significantly reduced 2H O2 by nearly four-fold and increased endothelial-derived nitric oxide bioavailability by nearly four-fold during reperfusion compared to controls (p < 0.01), which was confirmed in in vivo rat hind limb ischemia/reperfusion models. These results suggest that apocynin attenuates ischemia/reperfusion-induced cardiac contractile dysfunction and infarct size by inhibiting reactive oxygen species release from NADPH oxidase. Keywords: NADPH oxidase; Apocynin; Myocardial ischemia/ reperfusion, we established an in vivo rat hindlimb ischemia/ reperfusion; Hind limb ischemia/reperfusion; Nitric oxide; Hydrogen reperfusion injury model that directly measures reactive oxygen species peroxide; Leukocyte superoxide release levels in blood (i.e., hydrogen peroxide [H2O2]) and NO in real-time [4,7,8] from both femoral veins (with one limb subjected to ischemia/ Introduction reperfusion and the other serving as a sham control). H2O2 is an indirect Coronary heart disease is the leading cause of death worldwide index of superoxide (SO) release because SO dismutase rapidly, within seconds, converts SO to H O ; this process is enhanced under low pH [1]. The most effective therapeutic intervention for reducing infarct 2 2 size associated with myocardial ischemic injury is timely and effective conditions [9,10]. Our hind limb ischemia/reperfusion injury model is appropriate to measure H O and NO blood levels during ischemia/ reperfusion of blood flow back to the heart tissue by percutaneous 2 2 coronary intervention. However, the reperfusion of blood itself can reperfusion because the direct measurements are not feasible in the induce additional cardiomyocyte death that can account for up to coronary circulation of the isolated perfused rat heart model. We found that an inverse relationship exists between blood H O and NO levels 50% of the final infarct size [2]. Remarkably, after several decades of 2 2 in ischemia/reperfusion . Greater production of H O and reduction preclinical and clinical studies, there is still no effective therapy to 2 2 limit reperfusion-induced tissue death and improve post-reperfused of NO during reperfusion in hind limb ischemia/reperfusion closely cardiac function. Consequently, there is a great need to identify the correlates with a greater degree of post-reperfused cardiac dysfunction mechanism(s) responsible for myocardial ischemia/reperfusion injury. in myocardial ischemia/reperfusion [4,7,8].Therefore, quantifying blood reactive oxygen species release and NO levels in real-time during Ischemia/reperfusion injury is initiated in part by endothelial reperfusion is important to determine the initiating sources of reactive dysfunction, which occurs within 5 min of reperfusion. It is characterized oxygen species in ischemia/reperfusion and to develop potential by an increase in reactive oxygen species leading to endothelial nitric treatment strategies for ameliorating reperfusion injury. oxide synthase uncoupling, which in turn causes more reactive oxygen species production and limited endothelial-derived Nitric Oxide Although clinical trials suggest non-selective antioxidants do not (NO) bioavailability [2-4]. The reduced NO bioavailability leads to effectively attenuate reperfusion injury, this may be due to lack of compromised blood flow during reperfusion and increased leukocyte- endothelial interactions, which will exacerbate tissue damage. The time course of endothelial dysfunction in myocardial ischemia/reperfusion *Corresponding author: Lindon Young, Department of Bio-Medical Sciences, is similar to other vascular beds, such as hind limb ischemia/reperfusion Philadelphia College of Osteopathic Medicine (PCOM), 4170 City Avenue, Philadelphia, USA, Tel: 2158716832; Fax: 2158716869; E-mail: [email protected] and splanchnic ischemia/reperfusion [5,6]. The significance of this commonality is that compounds that attenuate endothelial dysfunction Received February 16, 2016; Accepted February 24, 2016; Published March 01, in the heart could be applied to other vascular beds such as pulmonary, 2016 kidney, liver, mesenteric and limb circulation. Therefore, this could Citation: Chen Q, Parker WC, Devine I, Ondrasik R, Habtamu T, et al. (2016) be clinically applied to prevent organ damage in various ischemia/ Apocynin Exerts Dose-Dependent Cardioprotective Effects by Attenuating Reactive Oxygen Species in Ischemia/Reperfusion. Cardiovasc Pharm Open Access 5: 176. reperfusion injury settings, such as organ transplantation, circulatory doi:10.4176/2329-6607.1000176 shock, prolonged tourniquet use and coronary bypass/balloon Copyright: © 2016 Chen Q, et al. This is an open-access article distributed under angioplasty. the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and In order to understand endothelial dysfunction during ischemia/ source are credited. Cardiovasc Pharm Open Access Volume 5 • Issue 2 • 1000176 ISSN: 2329-6607 CPO, an open access journal Citation: Chen Q, Parker WC, Devine I, Ondrasik R, Habtamu T, et al. (2016) Apocynin Exerts Dose-Dependent Cardioprotective Effects by Attenuating Reactive Oxygen Species in Ischemia/Reperfusion. Cardiovasc Pharm Open Access 5: 176. doi:10.4176/2329-6607.1000176 Page 2 of 7 specifically targeting the source of oxidative stress. Four enzymatic the thiols in NADPH oxidase. Moreover, apocynin may be a prodrug sources principally contribute to oxidative stress (i.e., reactive oxygen and thus needs to be activated by peroxidase-mediated oxidation to species) during reperfusion: NADPH oxidase, xanthine oxidase, diapocynin, its active oxidizing form, which is illustrated in Figure 2. uncoupled eNOS, and the mitochondrial electron transport chain. Specifically, the effects of apocynin oxidize the cysteine-196 position NADPH oxidases comprise a family of enzymes that initiates and of p47phox, a cytosolic component of NADPH oxidase that is activated recruits the other three sources as follows [11]: 1. NADPH oxidase 2 via phosphorylation by protein kinase C, which, in turn, inhibits the phox (Nox2) naturally produces SO/H2O2 upon the assembly of the cytosolic association of the p22 membrane subunit component of NADPH subunits (i.e., rac, p67phox, p47phox, and p40phox) with, the membrane oxidase and, therefore inhibit Nox2 assembly and subsequent SO subunits (i.e., p22phox and gp91phox); 2. It is expressed in many cells in the release, thereby decreased oxidative stress and tissue damage [21,22]. heart, such as vascular endothelium and cardiac myocytes, and is the We hypothesize that administration of selective NADPH oxidase principle source of SO release in leukocytes; 3. SO/H O release from 2 2 inhibitors, such as apocynin, will dose-dependently attenuate activated NADPH oxidase can open mitochondrial ATP-dependent blood H O and augment NO bioavailability in hindlimb ischemia/ potassium channels and/or mitochondria permeability transition pores, 2 2 reperfusion, and will decrease SO release from leukocytes and reduce which further lead to mitochondrial matrix alkalization, mitochondrial infarct size/area-at-risk in ischemia/reperfusion hearts, and thus electron transport chain uncoupling, and SO production [12]; 4. improving post-reperfused cardiac function. Overproduction of SO/H2O2 will also promote the transformation of xanthine dehydrogenase into xanthine oxidase [13,14]; 5. SO can Methods quench NO to form peroxynitrite anion, which in turn can promote eNOS uncoupling via the oxidation of the essential eNOS co-factor Animals tetrahydrobiopterin (BH ) to dihydrobiopterin (BH ) [15]. It has 4 2 All animal procedures were approved by the Institutional Animal been found in vitro that the increased ratio
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