Myocardial infarction (MI) has emerged as a major health problem during the past two decades. In the infarcted myocardium, loss of contractile myocardium and blood vessels is induced by MI. Cardiac repair at the site of myocyte loss preserves structural integrity and is integral to the heart's recovery. Angiogenesis, the growth of new blood vessels, is critical for cardiac repair following infarction. Impaired angiogenesis in the infarcted heart can lead to rupture and immature/weakened scar tissue. Stimulation of angiogenesis is beneficial in the treatment of coronary artery disease and cardiac repair. Angiogenesis is a tightly regulated process and numerous inducers of angiogenesis have been identified. There is growing recognition and experimental evidence that reactive oxygen species (ROS) plays an important role in stimulating cardiac angiogenesis. However, its underlying molecular mechanisms remain to be elucidated. Oxidative stress is developed in the infarcted heart, particularly in the infarcted myocardium during the early stage of MI, and is temporally and anatomically coincident with the formation of new vessels. The overall objective of this proposal is to explore the underlying mechanisms by which ROS promotes angiogenesis in the infarcted heart. Angiogenesis occurs through degradation of basement membranes/extracellular matrix (ECM) followed by endothelial cell proliferation and migration, tube formation and vessel maturation. Using an experimental MI model created by coronary artery ligation in Sprague-Dawley (SD) rats with pharmacological intervention;inducible nitric oxide synthase (iNOS) gene knockout mice;and cultured endothelial cells, we intend to fulfill the following specific aims:
Specific Aim 1 : To explore whether ROS promote angiogenesis by regulating endothelial cell migration and adhesion in the infarcted myocardium. Our hypotheses are: 1) ROS regulate the balance of matrix metalloproteinase (MMPs) and tissue inhibitors of MMPs (TIMPs), enhancing degradation of basement membrane and other ECM components, thus allowing endothelial cells to detach and migrate into the infarcted myocardium;and 2) ROS stimulate the expression of angiogenic integrins, thereby activating the integrin signaling pathway and promoting endothelial cell adhesion and migration.
Specific Aim 2 : To determine whether ROS elevate angiogenesis through triggering of endothelial cell proliferation and tube formation in the infarcted heart. Our hypothesis is that ROS activate the expressions of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), the major angiogenic mediators, and their signaling pathways in the infarcted myocardium, which, in turn, initiate endothelial cell proliferation and tube formation.
Specific Aim 3 : To examine whether ROS regulate angiogenesis via promoting vessel maturation and survival in the infarcted myocardium. Our hypothesis is that ROS activate the angiopoietin (Ang) signaling pathway in the infarcted myocardium, thus stimulating vessel maturation and stabilization.
The objective of this proposal is to investigate the cellular and molecular mechanisms regulating myocardial repair/remodeling following infarction (heart attack), particularly the role of reactive oxygen species on angiogenesis (new vessel formation) in the infarcted myocardium.
|Liu, Chang; Zhao, Wenyuan; Meng, Weixin et al. (2014) Platelet-derived growth factor blockade on cardiac remodeling following infarction. Mol Cell Biochem 397:295-304|
|Zhao, Tieqiang; Zhao, Wenyuan; Meng, Weixin et al. (2014) Vascular endothelial growth factor-C: its unrevealed role in fibrogenesis. Am J Physiol Heart Circ Physiol 306:H789-96|
|Meng, Weixin; Zhao, Wenyuan; Zhao, Tieqiang et al. (2014) Autocrine and paracrine function of Angiotensin 1-7 in tissue repair during hypertension. Am J Hypertens 27:775-82|
|Zhao, Tieqiang; Zhao, Wenyuan; Chen, Yuanjian et al. (2013) Platelet-derived growth factor-D promotes fibrogenesis of cardiac fibroblasts. Am J Physiol Heart Circ Physiol 304:H1719-26|
|Weber, Karl T; Sun, Yao; Bhattacharya, Syamal K et al. (2013) Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol 10:15-26|
|Zhao, Wenyuan; Zhao, Tieqiang; Chen, Yuanjian et al. (2013) Modification of oxidative stress on gene expression profiling in the rat infarcted heart. Mol Cell Biochem 379:243-53|
|Zhao, Wenyuan; Zhao, Tieqiang; Huang, Valerie et al. (2011) Platelet-derived growth factor involvement in myocardial remodeling following infarction. J Mol Cell Cardiol 51:830-8|