Investigation of therapeutic potential of exogenous ubiquitin following myocardial ischemia/reperfusion injury

外源性泛素治疗心肌缺血/再灌注损伤潜力的研究

• 批准号: 10265316
• 负责人: KRISHNA SINGH
• 金额: --
• 依托单位: JAMES H QUILLEN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265316
• 关键词: AMD3100; Address; Adult; Affect; Apoptosis; Area; Biochemical; Biology; CXCR4 gene; Cardiac; Cause of Death; Cell Proliferation; Cicatrix; Collagen; Data; Deposition; Development; Eukaryotic Cell; Event; Extracellular Matrix; Fibroblasts; Fibrosis; Gel; Heart; Human; In Vitro; Infarction; Inflammatory Response; Investigation; Ischemia; Knockout Mice; Lead; Left Ventricular Function; Leukemic Cell; MAPK3 gene; Measures; Modeling; Molecular; Molecular Weight; Mus; Myocardial Infarction; Myocardial Ischemia; Myocarditis; Myocardium; Myofibroblast; Outcome; Patient-Focused Outcomes; Patients; Peptides; Phagocytes; Phenotype; Play; Proteins; Regulation; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; Smooth Muscle Actin Staining Method; Specificity; Testing; Therapeutic; Toxic effect; Ubiquitin; VEGFA gene; Ventricular Remodeling; Veterans; base; beta-adrenergic receptor; cardioprotection; cell type; clinically relevant; cost effective; extracellular; healing; heart function; heart preservation; improved; improved outcome; in vivo; innovation; macrophage; migration; mouse model; mutant; neutrophil; novel; novel strategies; novel therapeutic intervention; receptor; regeneration potential; response; treatment strategy; wound

Ischemic heart disease (IHD) is a leading cause of death among veterans. Myocardial infarction (MI) is a serious outcome of IHD, and is generally attributable to the detrimental effects of myocardial ischemia/reperfusion (I/R) injury. Cardiac inflammation and extracellular matrix deposition (scar formation) are essential events in the cardiac remodeling post-MI. Therapeutic approaches targeting these events may hold promise for patients with MI. This proposal investigates the therapeutic potential of ubiquitin (UB; a small molecular weight protein typically associated with tagging proteins for proteasomal degradation) in myocardial remodeling following myocardial ischemia and I/R injury. The proposal is based on our novel observations that exogenous UB plays a protective role in β- adrenergic receptor-stimulated myocardial remodeling. In human THP1 leukemia cells, CXCR4 is identified as a receptor for extracellular UB. Our preliminary data using - i) isolated heart model of global ischemia/reperfusion (I/R; Langendorff model); and ii) in vivo myocardial I/R injury in mice now suggest a protective role of exogenous UB in myocardial remodeling following I/R injury. UB treatment decreased infarct size, reduced cardiac inflammatory response and improved heart function 3 days post-I/R. In vitro, UB treatment inhibited migration of neutrophils, and enhanced phagocytic activity of macrophages. In adult cardiac fibroblasts, UB treatment activated ERK1/2, and increased expression of vascular endothelial growth factor-A (VEGF-A). UB co-immunoprecipitated with CXCR4, and CXCR4 antagonism negated the effects of extracellular UB on ERK1/2 activation and VEGF-A expression. UB treatment augmented α-smooth muscle actin (a marker for myofibroblast differentiation) expression and collagen gel contractile activity of fibroblasts, while decreasing migration of fibroblasts into the wound area and inhibiting FBS-stimulated cell proliferation. These observations led us to hypothesize that exogenous UB, most likely acting via CXCR4, modulates cardiac inflammatory response and extracellular matrix biology by affecting phenotype and/or function of neutrophils, macrophages and fibroblasts, thereby playing a cardioprotective role in myocardial remodeling following ischemia and I/R injury. Aim 1 will investigate, in vivo, the therapeutic potential of exogenous UB in myocardial remodeling following myocardial ischemia and I/R injury. Aim 2 will examine, in vivo, the role of CXCR4 in modulation of cardioprotective effects of exogenous UB using CXCR4 antagonist, UB mutants and cell type-specific CXCR4 knockout mice. Aim 3 will investigate the cellular and molecular mechanisms by which exogenous UB affects cardiac inflammatory response and extracellular matrix biology to coordinate post-I/R cardioprotective response. The Innovation of this project lies in the investigation of therapeutic potential of exogenous UB in myocardial remodeling following myocardial ischemia and I/R injury (clinically relevant model). The proposed studies investigating the role of exogenous UB in cardiac inflammation and extracellular matrix biology may uncover novel strategies for the treatment of IHD.

缺血性心脏病（IHD）是退伍军人死亡的主要原因。心肌梗死（MI）