CC Chemokine Receptor-2 Deficiency Attenuates Oxidative Stress and Infarct Size Caused by Myocardial Ischemia-Reperfusion in Mice

arly reperfusion of an occluded coronary artery preserves myocardial viability and function by limiting the size of the myocardial infarct. 1,2 However, despite early reperfusion, myocardial ischemia-reperfusion (IR) injuries, including no reflow, stunning and reperfusion arrhythmias, sometimes occur, thereby attenuating the cardioprotective effect of reperfusion therapy. 3 Recent studies in experimental animals have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) attenuate IR injury independently of their lipid-lowering action. [4][5][6][7][8] Statins have pleiotropic effects, including improvement of endothelial function by increased nitric oxide (NO) bioavailability, 9 and antioxidant 10 and antiinflammatory actions, 11 which may explain their attenuation of IR injury. The experimental result of cardioprotection by statins has therapeutic implication for patients with acute coronary syndrome who will be treated with reperfusion therapy; however, the time at which statin treatment was administered before IR varied from hours to days, and the Circulation Journal Vol.70, December 2006 results are conflicting. 5,12 It is not clear whether acute administration of statins at the onset of ischemia or reperfusion will prevent or attenuate the IR injury.Oxidative stress plays an important role in IR injury, and antioxidants such as superoxide dismutase and catalase could limit the infarct size in IR. 13 Statins are known to decrease free radical generation in the vascular wall 14,15 and myocardium, 16 which suggests that statins may protect the ischemic myocardium from IR injury via suppression of oxygen-derived free radicals produced upon reperfusion. Among the statins, fluvastatin (FV) has a potent free radical scavenging property derived from its chemical structure 17 and the purpose of the present study was to elucidate the effects of acute administration of FV and the role of its antioxidant property on IR injury in rats. MethodsThe experimental procedures followed the approved guidelines for animal experimentation at the University of Toyama. Myocardial IRMale Wistar rats weighing 270-380 g (n=103) were intubated under ether anesthesia and ventilated using a rodent respirator. The heart was exposed by left thoracotomy and the left coronary artery was ligated 2-3 mm from its origin Background Three-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are known to attenuate myocardial ischemia-reperfusion (IR) injury. Fluvastatin (FV) has a potent free radical scavenging action, but it is unclear whether the timing of FV administration could affect its cardioprotective effect or if the antioxidant property of FV might attenuate IR injury. Methods and Results IR was induced in rats by left coronary artery occlusion for 30 min followed by 24-h reperfusion. The rats were divided into 4 groups: oral FV group (10 mg/kg per day for 2 weeks before ischemia); iv, FV group (10 mg/kg) before ischemia; iv, FV group (10 mg/kg) before reperfusion; and control gr...

Section: Antioxidant Property Of Fvcontrasting

confidence: 68%

Early Administration of Fluvastatin, but not at the Onset of Ischemia or Reperfusion, Attenuates Myocardial Ischemia-Reperfusion Injury Through the Nitric Oxide Pathway Rather Than Its Antioxidant Property

Matsuki

Igawa

Nozawa

et al. 2006

“…[7][8][9] Physiological concentrations of NO produced from endothelial NO synthase (eNOS) or NO donors exert significant cardioprotective effects, whereas the reaction between NO and ROS produces peroxynitrite and results in oxidative and nitrative tissue injury. [7][8][9][10][11][12][13] Evidence from several model systems supports the notion that NO radicals cause myocardial damage in MIR, 7,8,[12][13][14][15] whereas a small amount of NO exerts a cytoprotective effect in the reperfused heart. 11,12,16,17 The dynamics of oxidative stress up to 48 h after MIR remain unclear because of the difficulties associated with monitoring oxidation in vivo.…”

mentioning

confidence: 72%

“…[7][8][9][10] Though NO itself is not toxic and does not induce tissue injury, even at a high concentration, the reaction between NO and ROS produces peroxynitrite and results in oxidative and nitrative tissue injury. [8][9][10][11][12][13] Huang et al showed that the inhibition of iNOS activity blocks the increase in the number of leukocytes that synthesize ROS after MIR. 40 In the present study, we demonstrated that the urinary and tissue biopyrrins concentrations were obviously reduced with nonselective suppression of NOS expression.…”

Section: Discussionmentioning

confidence: 99%

Biphasic Elevation of Bilirubin Oxidation During Myocardial Ischemia Reperfusion

Yamamoto

Maeda

Hirose

et al. 2008

lthough therapeutic intervention or coronary artery bypass grafting can recover coronary blood flow, myocardial damage after blood flow reperfusion, namely myocardial ischemia reperfusion (MIR) injury, remains to be resolved. Among the factors affecting MIR, oxidative stress might play an important role in both the myocardial injury and the cardiac events after reperfusion therapy. 1 Oxidative stress induced by superoxide generated via the xanthine oxidase system and infiltrating inflammatory cells is the major proposed mechanism of MIR progression. [2][3][4][5] We have reported that reactive oxygen species (ROS) influence the opening of the mitochondrial permeability transition pore in myocardial cells, which led to progression of myocardial infarction (MI) in a rat MIR model. 6 Moreover, total nitric oxide (NO) synthesis in the reperfused heart was increased in previous investigations. 7-9 Physiological concentrations of NO produced from endothelial NO synthase (eNOS) or NO donors exert significant cardioprotective effects, whereas the reaction between NO and ROS produces peroxynitrite and results in oxidative and nitrative tissue injury. [7][8][9][10][11][12][13] Evidence from several model systems supports the notion that NO radicals cause myocardial damage in MIR, 7,8,[12][13][14][15] whereas a small amount of NO exerts a cytoprotective effect in the reperfused heart. 11,12,16,17 The dynamics of oxidative stress up to 48 h after MIR remain unclear because of the difficulties associated with monitoring oxidation in vivo. This period is considered critical in both cardiac surgery and therapeutic intervention, so more sensitive and reliable markers of in vivo oxidative stress are required.Bilirubin is an intrinsic antioxidant that quenches radicals under several inflammatory conditions. 18-21 Its synthesis is regulated by the rate-limiting enzyme, heme oxygenase-1 (HO-1), which is rapidly induced by oxidative stress and inflammatory reactions caused by factors such as cytokines, ischemia and NO. [22][23][24][25][26][27][28][29] Bilirubin generates several hydrophilic metabolites called biopyrrins upon oxidation and these can be detected using the anti-bilirubin monoclonal antibody 24G7. 30,31 Biopyrrins are immediately excreted in urine because of their hydrophilic properties and thus can reflect the severity of oxidative stress. 25,[32][33][34][35][36][37][38] Biopyrrin synthesis reflects NO radicals, 25 so urinary biopyrrin levels can indicate ongoing changes in oxidative stress in vivo and thus function as a marker of oxidative stress.The time course of urinary and tissue biopyrrin levels in rat models of cardiac transplantation and hepatic ischemia reperfusion has been investigated. 25,32 A cardiac transplantation study showed that levels of urinary biopyrrins become more rapidly and sensitively elevated than either urinary 8-hydroxy-2'-deoxyguanosine or serum troponin-T during Biphasic Elevation of Bilirubin Oxidation During Myocardial Ischemia ReperfusionMasaki Yamamoto, MD; Hironori Maeda, MD; Nobuyuki...

“…[12][13][14][15] Recently, it has Circulation Journal Vol. 72, October 2008 been demonstrated that the expression of MCP-1 in the myocardium increases during the early phase of MI, 5,10,[16][17][18] and that targeted deletion or pharmacological inhibition of MCP-1 prevents early post-MI LV remodeling. 17,19 However, the role of myocardial MCP-1 during the chronic phase of MI remains to be elucidated.…”

mentioning

confidence: 99%

Angiotensin-Receptor Blockade Reduces Border Zone Myocardial Monocyte Chemoattractant Protein-1 Expression and Macrophage Infiltration in Post-Infarction Ventricular Remodeling

Kohno

Anzai

Naito

et al. 2008

eft ventricular (LV) remodeling after myocardial infarction (MI) is a process producing changes in LV geometry, such as progressive cavity dilatation, following infarct expansion, and it contributes to the development of heart failure (HF). 1 Inhibition of the cardiac renin -angiotensin system (RAS) prevents both LV remodeling and the transition from a compensatory state to decompensated HF after MI. [1][2][3][4] However, the precise mechanisms for the development of LV remodeling and the benefits of RAS inhibition have not been fully elucidated.Accumulating evidence suggests that the inflammatory response is a key component of the structural deterioration associated with post-MI LV remodeling. [5][6][7][8][9][10][11] Monocyte chemoattractant protein-1 (MCP-1), a C-C chemokine with potent chemotactic and activating effects on monocytes, is known to make a major contribution to the pathogenic role of inflammation in cardiovascular diseases. MCP-1 contributes to the progression of atherosclerosis and vascular remodeling after coronary angioplasty. [12][13][14][15] Recently, it has Circulation Journal Vol. 72, October 2008 been demonstrated that the expression of MCP-1 in the myocardium increases during the early phase of MI, 5,10,[16][17][18] and that targeted deletion or pharmacological inhibition of MCP-1 prevents early post-MI LV remodeling. 17,19 However, the role of myocardial MCP-1 during the chronic phase of MI remains to be elucidated.The border zone region has been defined as uniquely dysfunctional myocardium, adjacent to an infarct, that is normally perfused, but remains hypocontractile. The progressive extension of border zone myocardium to normally perfused myocardium during the chronic phase of MI leads to late-phase HF following MI. 20 Of the inflammatory cells, macrophages are present in highest numbers and for longest period in the border zone and infarcted regions. 7,21 Macrophages play a central role in the pathogenesis of fibrosis, therefore it is plausible that persistent macrophage infiltration might contribute to the expansion of myocardial fibrosis in the border zone region, leading to progressive LV dysfunction.RAS participates in the inflammatory response, and angiotensin II (AngII) stimulates production of MCP-1 in a variety of cells via AngII type 1 receptors in vivo and in vitro. [22][23][24][25][26][27][28] A previous study has demonstrated increased angiotensin-converting enzyme expression in the border zone and infarcted myocardium. 29 We therefore hypothesized that increased MCP-1 expression and macrophage infiltration would be detectable in the border zone, as well as infarcted region, during the chronic phase of MI, and that inhibition of angiotensin signaling by an AngII type 1 re- Background Monocyte chemoattractant protein-1 (MCP-1) is a key mediator of left ventricular (LV) remodeling during the early phase of myocardial infarction (MI). The hypothesis tested was that myocardial MCP-1 expression would increase during the chronic phase of MI and an angiotensin-II type 1 rece...