Restoration of Senescent Cardiac Angiogenic Potential

恢复衰老心脏血管生成潜能

• 批准号: 7077593
• 负责人: Jay M. Edelberg
• 金额: $ 33.1万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077593
• 关键词: aging; angiogenesis; angiopoietins; cardiac myocytes; cardiovascular function; echocardiography; epidermal growth factor; gene expression; growth factor receptors; homologous transplantation; laboratory mouse; laboratory rat; myocardial infarction; myocardium; platelet derived growth factor; polymerase chain reaction; tissue /cell culture; transfection; vascular endothelial growth factors; vascular endothelium; western blottings

Angiogenic potential in the aging heart is depressed. Preliminary studies have revealed that alterations in aging endothelial cells result in the dysregulation of a cardiac myocyte-epidermal growth factor (EGF)- platelet-derived growth factor (PDGF) pathway that underlies the decline in senescent cardiac angiogenic activity. Endothelial cells of the young murine heart express the EGF receptor (EGFR) which mediates the cardiac myocyte-induced endothelial expression of PDGF B. This leads to the generation of PDGF AB that has been demonstrated to regulate the activity of endothelial cells in the heart. Endothelial cells of the aging heart lack EGFR and do not express PDGF B when cultured in the presence of cardiac myocytes Adenoviral-mediated expression of EGFR specifically restores PDGF B induction in the older endothelial cells. In vivo studies revealed that reconstitution of the PDGF B-dependent pathways by delivery of EGFR or PDGF AB restores senescent cardiac angiogenic function moreover, this pro-angiogenic pathway us cardioprotective, reducing the extent of myocardial infarction following coronary ligation. Taken together, these data strongly support the hypothesis that reconstitution of the PDGF B-mediated pathways in the endothelial cells of the aging heart will restore senescent cardiac angiogenic function. The long-range goal of this project is to specifically enhance angiogenic activity in the aging heart by the molecular restoration of cardiac endothelial cell function. The EGFR domains mediating PDGF B induction will be defined and restored in older cardiac endothelial cells to promote the long-term specific reconstitution of the senescent cardiac pro-angiogenic pathways. In addition, the set of endothelial genes augmenting the pro-angiogenic actions of PDGF AB will be defined as a means of increasing the potency of this approach in the restoration of senescent cardiac angiogenic activity. The functional significance of these strategies will be confirmed by their ability to promote cardiac angiogenic function and protect the aging heart from myocardial infarction. Overall these studies will facilitate the development of novel approaches for the treatment and possible prevention of cardiovascular diseases in older persons.

衰老心脏中的血管生成潜力抑郁。初步研究表明，衰老内皮细胞的变化导致心肌细胞表皮生长因子（EGF） - 血小板衍生的生长因子（PDGF）途径的失调，这是衰老心脏血管生成活性下降的基础。年轻鼠心的内皮细胞表达EGF受体（EGFR），该EGF受体（EGFR）介导心肌细胞诱导的PDGF B的内皮表达。这导致已证明PDGF AB的产生，该PDGF AB已被证明可以调节心脏内皮细胞的活性。衰老心脏的内皮细胞缺乏EGFR，当在腺炎病毒介导的EGFR的表达中培养时，EGFR培养时不会表达PDGF B，特异性恢复了较旧的内皮细胞中的PDGF B诱导。体内研究表明，通过递送EGFR或PDGF AB来重建PDGF B依赖性途径，还可以恢复衰老的心脏血管生成功能，此外，这种亲血管生成途径US心脏保护途径，降低了冠状动脉结扎后心肌梗塞的程度。综上所述，这些数据强烈支持以下假设：在衰老心脏的内皮细胞中，PDGF B介导的途径重建将恢复衰老心脏血管生成功能。该项目的远距离目标是通过心脏内皮细胞功能的分子恢复来特异性增强衰老心脏的血管生成活性。介导PDGF B诱导的EGFR结构域将在较旧的心脏内皮细胞中定义并恢复，以促进衰老心脏亲血管生成途径的长期特异性重构。此外，增强PDGF AB的促血管生成作用的内皮基因集将被定义为增加这种方法在恢复衰老心脏血管生成活性时的效力。这些策略的功能意义将通过它们促进心脏血管生成功能并保护衰老心脏免受心肌梗塞的能力来证实。总体而言，这些研究将有助于发展新颖的方法，以预防老年人的心血管疾病。