Dong Wang

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Journals/Publications

• Saleem, S., Wang, D., Zhao, T., Sullivan, R. D., & Reed, G. L. (2022). Matrix Metalloproteinase-9 Expression is Enhanced by Ischemia and Tissue Plasminogen Activator and Induces Hemorrhage, Disability and Mortality in Experimental Stroke. Neuroscience.
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  We made significant changes accordingly from the previous version. This paper will be submitted in the early of year 2023.
• Sun, Y., Tripathi, R., Mehta, R. M., Fan, M. T., Sullivan, R. D., Wang, D., Reed, G. L., & Gladysheva, I. P. (2018). Changes in the Natriuretic Peptide Activating Enzyme Corin During Acute Myocardial Infarction: Relationship to ANP, BNP and Myocardial Injury: AJPA_2018_171. AJPA.
• Gladysheva, I., Reed, G., Wang, D., Sullivan, R., Fan, M. T., Mehta, R. M., Tripathi, R., & Sun, Y. (2018). Dynamic changes in plasma corin levels are inversely associated with cardiac corin in acute experimental myocardial infarction: HYPE201811046. Hypertension.
• Wang, D. (2020). Corin Overexpression Reduces Myocardial Infarct Size and Modulates Cardiomyocyte Apoptotic Cell Death. Int J Mol Sci, 21(10), 3456. doi:10.3390/ijms21103456
• Wang, D., Gladysheva, I. P., Sullivan, R. D., Fan, T. M., Mehta, R. M., Tripathi, R., Sun, Y., & Reed, G. L. (2018). Increases in plasma corin levels following experimental myocardial infarction reflect the severity of ischemic injury. PloS one, 13(9), e0202571.
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  Following acute myocardial infarction, clinical studies show alterations in the blood levels of corin, a cardiac-selective activator of the natriuretic peptides pro-atrial natriuretic peptide (pro-ANP) and pro-B-type natriuretic peptide (pro-BNP). However, the temporal changes in circulating and cardiac corin levels and their relationships to the severity of myocardial infarction have not been studied. The main objective of this study was to examine the relationship between cardiac and circulating corin levels and their association with cardiac systolic function and infarct size during the early phase of acute myocardial infarction (
• Wang, D., Gladysheva, I. P., Wang, D., Tripathi, R., Sun, Y., Sullivan, R. D., Reed, G. L., Gladysheva, I. P., & Fan, T. M. (2017). Enhanced heart failure, mortality and renin activation in female mice with experimental dilated cardiomyopathy.. PloS one, 12(12), e0189315. doi:10.1371/journal.pone.0189315
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  Dilated cardiomyopathy (DCM) is the major cause of heart failure affecting both women and men. Limited clinical studies show conflicting data in sex-related differences in the progression of dilated cardiomyopathy and heart failure (HF) outcomes. We examined the comparative sex-related progression of cardiomyopathy and the development of HF (at 4, 7, 13 weeks of age) in a well-established, transgenic mouse model of DCM that recapitulates the progressive stages of human HF. By 13 weeks of age, female mice with DCM had more severe left ventricular systolic dysfunction, left ventricular dilation and wall thinning (P
• Wang, D., Gladysheva, I. P., Wang, D., Tripathi, R., Sun, Y., Sullivan, R. D., Reed, G. L., Mehta, R. M., Gladysheva, I. P., & Fan, T. M. (2017). Abstract P349: Plasma Corin Levels Reflect Dynamic Changes in Cardiac Expression Induced by Experimental Acute Myocardial Infarction. Hypertension.
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  Introduction: Corin is a cardiac membrane protease that activates pro-ANP and pro-BNP. Changes in circulating corin levels have been linked to poor clinical outcomes following acute myocardial infa...
• Wang, D., Gladysheva, I. P., Wang, D., Tripathi, R., Sullivan, R. D., Reed, G. L., Gladysheva, I. P., & Fan, T. M. (2016). Depressed Corin Levels Indicate Early Systolic Dysfunction Before Increases of Atrial Natriuretic Peptide/B-Type Natriuretic Peptide and Heart Failure Development.. Hypertension (Dallas, Tex. : 1979), 67(2), 362-7. doi:10.1161/hypertensionaha.115.06300
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  Dilated cardiomyopathy is a major cause of heart failure (HF) that affects millions. Corin cleaves and biologically activates pro-atrial natriuretic peptide (pro-ANP) and pro-B-type natriuretic peptide (pro-BNP). High corin levels reduce the development of systolic dysfunction and HF in experimental dilated cardiomyopathy. Yet, patients with significant HF unexpectedly show low corin levels with high plasma ANP/BNP levels. Therefore, we examined the relationship between cardiac corin expression, ANP/BNP levels, and the stages of HF. We used a well-established, dilated cardiomyopathy model to evaluate gene and protein expression as mice longitudinally developed Stages A-D HF. Cardiac systolic function (ejection fraction) continuously declined over time (P
• Wang, D., Wang, D., Singh, S., Reed, G. L., & Houng, A. K. (2016). Physiologic variations in blood plasminogen levels affect outcomes after acute cerebral thromboembolism in mice: a pathophysiologic role for microvascular thrombosis.. Journal of thrombosis and haemostasis : JTH, 14(9), 1822-32. doi:10.1111/jth.13390
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  Essentials Physiologic variations in blood plasminogen (Pg) levels may affect ischemic stroke outcomes. We tested Pg effects in a model with translational relevance to human thromboembolic stroke. A dose-response exists between Pg levels and brain injury, fibrinolysis, barrier breakdown. Higher Pg levels reduce microvascular thrombosis and improve outcomes in ischemic stroke..Background and Objectives Plasminogen appears to affect brain inflammation, cell movement, fibrinolysis, neuronal excitotoxicity, and cell death. However, brain tissue and circulating blood plasminogen may have different roles, and there is wide individual variation in blood plasminogen levels. The aim of this study was to determine the integrated effect of blood plasminogen levels on ischemic brain injury. Methods We examined thromboembolic stroke in mice with varying, experimentally determined, blood plasminogen levels. Ischemic brain injury, blood-brain barrier breakdown, matrix metalloproteinase-9 expression and microvascular thrombosis were determined. Results Within the range of normal variation, plasminogen levels were strongly associated with ischemic brain injury; higher blood plasminogen levels had dose-related, protective effects. Higher plasminogen levels were associated with increased dissolution of the middle cerebral artery thrombus. Higher plasminogen levels decreased blood-brain barrier breakdown, matrix metalloproteinase-9 expression and microvascular thrombosis in the ischemic brain. In plasminogen-deficient mice, selective restoration of blood plasminogen levels reversed the harmful effects of plasminogen deficiency on ischemic brain injury. Specific inhibition of thrombin also reversed the effect of plasminogen deficiency on ischemic injury by decreasing microvascular thrombosis, blood-brain barrier breakdown, and matrix metalloproteinase-9 expression. Conclusions Variation in blood plasminogen levels, within the range seen in normal individuals, had marked effects on experimental ischemic brain injury. Higher plasminogen levels protected against ischemic brain injury, and decreased blood-brain barrier breakdown, matrix metalloproteinase-9 expression, and microvascular thrombosis. The protective effects of blood plasminogen appear to be mediated largely through a decrease in microvascular thrombosis in the ischemic territory.
• Wang, D., Wang, D., Reed, G. L., & Houng, A. K. (2015). Abstract W P258: Alpha-2-antiplasmin Inactivation Reduces Brain Injury, Hemorrhage and Death Following Ischemic Stroke. Stroke, 46.
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  INTRODUCTION: High levels of a2-antiplasmin (a2AP) have been linked to failure of tissue plasminogen activator therapy, but the overall role of a2AP in ischemic stroke is poorly understood. HYPOTHESIS: We examined the hypothesis that a2AP may contribute to the pathogenesis of ischemic stroke. METHODS: The effects of a2AP blood levels and a2AP inactivation on stroke outcomes were examined in a model of middle cerebral artery thromboembolism. RESULTS: There was a dose-dependent relationship between a2AP blood levels and stroke outcomes. Deficiency of circulating a2AP had protective effects in ischemic stroke; it increased dissolution of the culprit middle cerebral artery thromboembolus (p
• Wang, D., Gladysheva, I. P., Wang, D., Sullivan, R. D., Reed, G. L., Houng, A. K., Gladysheva, I. P., & Fan, T. M. (2014). Atrial natriuretic peptide affects cardiac remodeling, function, heart failure, and survival in a mouse model of dilated cardiomyopathy.. Hypertension (Dallas, Tex. : 1979), 63(3), 514-9. doi:10.1161/hypertensionaha.113.02164
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  Dilated cardiomyopathy is a frequent cause of heart failure and death. Atrial natriuretic peptide (ANP) is a biomarker of dilated cardiomyopathy, but there is controversy whether ANP modulates the development of heart failure. Therefore, we examined whether ANP affects heart failure, cardiac remodeling, function, and survival in a well-characterized, transgenic model of dilated cardiomyopathy. Mice with dilated cardiomyopathy with normal ANP levels survived longer than mice with partial ANP (P
• Gladysheva, I. P., Wang, D., Wang, D., Reed, G. L., Mohamad, A. A., Mcnamee, R. A., Houng, A. K., Gladysheva, I. P., & Fan, T. M. (2013). Corin overexpression improves cardiac function, heart failure, and survival in mice with dilated cardiomyopathy.. Hypertension (Dallas, Tex. : 1979), 61(2), 327-32. doi:10.1161/hypertensionaha.112.193631
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  Heart failure, caused by dilated cardiomyopathy and other cardiac disorders such as hypertension, is a major public health problem with high morbidity and mortality. Corin, a cardiac enzyme that cleaves natriuretic peptides, is a promising biomarker of cardiomyopathy and heart failure, but its functional role in these processes is not understood. We evaluated the potential effects of corin in mice with a well-characterized model of dilated cardiomyopathy. Mice with dilated cardiomyopathy developed heart failure, reduced contractile function, cardiac fibrosis, and accelerated mortality in the setting of low corin expression. In wild-type mice, transgenic, cardiac-targeted, overexpression of corin enhanced cyclic guanosine monophosphate and blood pressure responses to pro-atrial natriuretic peptide, but did not affect heart size, contractility, body weights, survival, and blood pressure. In mice with dilated cardiomyopathy, corin overexpression significantly reduced the development of myocardial fibrosis (P
• Wang, D., Wang, D., Reed, G. L., & Houng, A. K. (2013). Abstract TP274: Inactivation of Serpinf2 Saves Lives, Prevents Disability and Hemorrhage in Experimental Thromboembolic Ischemic Stroke. Stroke, 44.
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  More than 15 million individuals suffer ischemic stroke each year. High levels of serpinf2 (Sf2, a2-plasmin inhibitor, a2-antiplasmin) have been identified as a potential risk factor for human ischemic stroke. Methods: We examined the integrated effects of sf2 in a thromboembolic MCA stroke model with translational relevance to human disease. Using a blinded observer, neuronal cell death was quantified by TTC staining; hemorrhage and brain swelling were determined by planimetry. Immunohistochemistry was used to assess apoptosis, matrix metalloproteinase 9 expression and breakdown of the blood brain barrier. Results: Increasing the levels of sf2 caused larger infarctions by comparison to control mice (51% larger, p 12 hrs.) showed that sf2-i reduced stroke infarct size by comparison to control mice or TPA treated mice (p Conclusions: Sf2 significantly enhances brain injury in ischemic stroke. Since inactivation of Sf2 prevents disability, hemorrhage and death it may prove to be a safe and effective strategy for treating acute ischemic stroke.
• Wang, D., Wang, D., Reed, G. L., & Houng, A. K. (2013). Abstract WP254: The Contribution of Serpinf2 to Tissue Plasminogen Activator Therapy for Stroke: Effects on Neuronal Cell Death, Brain Swelling, Breakdown of the Blood Brain Barrier and Mortality. Stroke, 44.
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  For poorly understood reasons, tissue plasminogen activator (TPA) therapy for ischemic stroke is limited by a narrow therapeutic window and by toxicities including hemorrhage. In this study we investigated the contribution of serpinf2 (Sf2, a2-plasmin inhibitor, a2-antiplasmin) to the success and complications of TPA therapy. Methods: Ischemic stroke was induced by MCA thromboembolism in anesthetized mice. Infarct size, hemorrhage and swelling were examined by a blinded observer. Breakdown of the blood brain barrier, MMP-9 expression and apoptosis were determined by quantitative immunohistochemistry. Results: TPA treatment within 15 min. of ischemia significantly reduced infarction (p Conclusion: Sf2 reduces TPA’s efficacy and enhances toxicity by increasing stroke infarct size and brain swelling. In contrast, inactivation of Sf2 increased the therapeutic window for TPA, which in turn reduced infarction, brain swelling and hemorrhage. Sf2-i also significantly reduced break down of the blood brain barrier and apoptosis. Thus inactivation of Sf2 may increase the therapeutic value of TPA.
• Wang, D., Wang, D., Reed, G. L., & Houng, A. K. (2012). Abstract 4031: Tissue Plasminogen Activator Exerts Neurotoxic Effects Despite Successful Thrombus Dissolution in Ischemic Stroke. Stroke, 43.
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  Introduction: Ischemic stroke, caused by thrombotic arterial occlusion, is a leading cause of death and disability. Tissue plasminogen activator (TPA) reduces neurological disability post-stroke in humans but its therapeutic effect is limited by ischemic time and hemorrhagic risk. Of concern, mechanical occlusion models of stroke suggest that TPA exerts direct neurotoxic effects, but the relevance of these non-thrombotic models to human stroke is controversial. Methods: We examined the integrated effects of TPA dose and ischemic time in a thromboembolic model of middle cerebral artery (MCA) stroke with translational relevance to human stroke. In anesthetized mice, blood flow was assessed by laser Doppler, neuronal cell death was quantified by TTC staining and thrombus dissolution was measured with 125I-fibrin. Results: MCA thromboembolism reduced ipsilateral hemispheric blood flow by ∼80%. Control, placebo-treated, mice had significant infarcts (27.5±2.8%) and limited thromboembolus dissolution (20.6 ± 2.5%). Standard dose TPA given after 15 min. of ischemia, dissolved the thromboembolus (63.3±3.6 %) and reduced neuronal cell death (1.3± 0.7 %) without increasing hemorrhage (0.02 ± 0.02 %). TPA given after 1 hr. or 2.5 hrs. of ischemia also extensively dissolved the MCA thromboembolus (69.5 ± 8.1% and 64.6 ± 1.5%, respectively, p Conclusions: TPA dissolved MCA thromboemboli independent of duration of ischemia. However, TPA only reduced stroke size within a narrow time window (15 min.); after 2.5 hrs., TPA markedly enhanced neuronal cell death and brain hemorrhage. Thus, in a model of thromboembolic stroke with translational relevance, despite successful dissolution of thromboemboli, TPA exerts neurotoxic effects related to dose and duration of ischemia.

Presentations

• Wang, D. (2018, November). Corin: more than a biomarker in ischemic heart disease. Translational Cardiovascular Research Collaborative. Biomedical Sciences Partnership Building: UA COM-Phoenix.

Others

• Wang, D. (2018, September). uncover the molecular mechanisms underlying the protective role of corin in ischemic heart disease.
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  I had made significant progress in uncovering the molecular mechanisms underlying the protective role of corin in ischemic heart disease. By using corin-1052 mouse line, which specifically overexpress enzymatically inactive corin mutant in the cardiac cells (loss of pro-ANP cleavage capability), I found that that corin can induce cardioprotective effects independent of its enzymatic activity after MI when compared to functional corin-tg mice. I further identified grp78 and grp94 as potential targets, which may be responsible for corin’s cardiac protection through an enzymatic activity independent mechanism.