Angiogenesis, defined as formation of new blood vessels, is a physiological process necessary for embryonic development and wound repair. Angiogenesis is also an important component of various pathologic events such as tissue ischemia, cancer, diabetic retinopathy, and chronic inflammatory states including atherosclerosis. Among the key events leading to angiogenesis is generation of reactive oxygen species (ROS) such as superoxide anions and hydrogen peroxide which play a key role in physiological and pathophysiological states. LOX-1, a lectin-like ox-LDL receptor, is responsible for binding and uptake of ox-LDL in endothelial cells. It has been well documented that the activation of LOX-1 itself can stimulate the formation of ROS and initiate a cascade of redox-sensitive signaling events. We postulate that oxidized LDL (ox-LDL) at low concentrations activates LOX-1 in endothelial cells, induces low levels of ROS release and initiates the angiogenic response.
Our specific aims i n this proposal are:
Aim # 1: To study the effect of oxidized LDL (ox-LDL) on angiogenesis- These studies will be done in human coronary artery endothelial cells, in an aortic ring model of angiogenesis, as well as in wild-type and LOX-1 knock out (KO) mice.
Aim # 2: To define the mechanisms of ox-LDL-induced angiogenic response- These studies will involve a number of specific inhibitors, LOX-1 antibody, siRNA against LOX-1, and upregulation of LOX-1, and will involve state-of-art molecular biology approaches. Further, to define the mechanism of the effects of ox-LDL, microarray technology will be utilized to identify genes that are up-regulated and down-regulated during angiogenesis. The strengths of the proposal are: 1. The PI has strong background on angiogenesis and LOX-1 research. 2. The PI has LOX-1 KO mice in his possession. 3. Availability of well trained molecular biologist well-versed in most aspects of the research. 4. One of the PI's team members has extensive experience in microarray technology. Significance: Understanding of the basis of formation of neovasculature may provide novel information on the basis of atherogenesis, especially in the development of unstable lesions. Information gained from this study may also have relevance in the development of cancers which are dependent of neovasculature for their growth.
Hardening of the arteries (also known as atherosclerosis) is the cause of heart attacks. As the area covered with atherosclerosis grows, there is formation of small new blood vessels;a process called angiogenesis. Angiogenesis is caused in part by oxygen-derived molecules called reactive oxygen species (ROS). Our work has shown that ROS stimulate a receptor for oxidized cholesterol called LOX- 1. The proposed experiments are designed to test the concept that oxidized cholesterol at low concentration activates LOX-1, induces low levels of ROS release and initiates angiogenesis. In contrast, high concentration of ROS causes much LOX-1 expression and cell injury. To confirm the role of LOX-1 in angiogenesis, we will use specialized mice that lack the LOX-1. In the second set of experiments, we will study the underlying mechanisms of angiogenesis by examining changes in genes. Information from this study may be important in understanding the development of atherosclerosis and certain cancers that are dependent of angiogenesis.
|Wang, Xian-Wei; Zhang, Fen-Xi; Yang, Fen et al. (2016) Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro. Acta Pharmacol Sin 37:1349-1358|
|Ayyadevara, Srinivas; Mercanti, Federico; Wang, Xianwei et al. (2016) Age- and Hypertension-Associated Protein Aggregates in Mouse Heart Have Similar Proteomic Profiles. Hypertension 67:1006-13|
|Mathur, Pankaj; Ding, Zufeng; Saldeen, Tom et al. (2015) Tocopherols in the Prevention and Treatment of Atherosclerosis and Related Cardiovascular Disease. Clin Cardiol 38:570-6|
|Wang, Wei; Lin, Li-Li; Guo, Jin-Min et al. (2015) Heavy ethanol consumption aggravates the ischemic cerebral injury by inhibiting ALDH2. Int J Stroke 10:1261-9|
|Ding, Zufeng; Liu, Shijie; Deng, Xiaoyan et al. (2015) Hemodynamic shear stress modulates endothelial cell autophagy: Role of LOX-1. Int J Cardiol 184:86-95|
|Ding, Zufeng; Liu, Shijie; Wang, Xianwei et al. (2015) Hemodynamic shear stress via ROS modulates PCSK9 expression in human vascular endothelial and smooth muscle cells and along the mouse aorta. Antioxid Redox Signal 22:760-71|
|Wang, Xianwei; Guo, Zhikun; Ding, Zufeng et al. (2015) Endothelin-1 upregulation mediates aging-related cardiac fibrosis. J Mol Cell Cardiol 80:101-9|
|Ding, Zufeng; Liu, Shijie; Wang, Xianwei et al. (2015) Lectin-like oxidized low-density lipoprotein receptor-1 regulates autophagy and Toll-like receptor 4 in the brain of hypertensive mice. J Hypertens 33:525-33; discussion 533|
|Mehta, Jawahar L; Mercanti, Federico; Stone, Annjannette et al. (2015) Gene and microRNA transcriptional signatures of angiotensin II in endothelial cells. J Cardiovasc Pharmacol 65:123-9|
|Ding, Zufeng; Liu, Shijie; Wang, Xianwei et al. (2015) Lectin-like ox-LDL receptor-1 (LOX-1)-Toll-like receptor 4 (TLR4) interaction and autophagy in CATH.a differentiated cells exposed to angiotensin II. Mol Neurobiol 51:623-32|
Showing the most recent 10 out of 24 publications