: Hypertension is the most prevalent disease in the western world and is a major cause of stroke, renal failure and myocardial infarction. In patients as well as in animal models of hypertension an increased thickness of the smooth muscle cell layer of arterioles is common. Because thickened walls of resistance vessels may act as a vascular amplifier to raise blood pressure, factors that regulate the growth of micro-vessels may contribute to the development of hypertension. Angiotensin II (ang II) is a multifunctional peptide that plays a fundamental role in physiological processes controlling blood pressure and in pathological mechanisms underlying vascular disease. There is evidence, that ang II effects on the vasculature involve other growth factors. IGF I act at the S phase of the cell cycle, it is a critical regulator of cell growth and indeed IGF I acting via its receptor (IGF IR) has a central role in modulating vascular smooth muscle cell (VSMC) proliferation. Ang 11 infusion increases IGF IR expression and smooth muscle cell replication in rat mesenteric resistance arteries. The long-term goal of this project is to determine the role of IGF IIIGF IR system in ang 11-induced VSMC growth in hypertension triggered resistance artery remodeling.
The specific aims of this proposal are:1. To document that ang II upregulates IGF IR in a pressor-independent mechanism in mesenteric arteries and to examine if upregulated IGF IR is associated with smooth muscle cell proliferation in vivo.2. To determine if a signaling pathway involving Ras, RacI and NADPH oxidase generates ROS that activate SGK and NF-KB leading to increased IGF JR transcription and VSMC proliferation.3. To demonstrate that increased expression of IGF JR leads to p27 down-regulation, up-regulation of cdk4 and cyclin DI and cell cycle progression in response to ang II.4. To demonstrate that ang II-induced proliferation of VSMC is blunted by a null mutation of the IGF IR in the vasculature.Our results should have important practical consequences for the development of therapies to modulate vascular remodeling in hypertension

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070762-04
Application #
6737503
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Lin, Michael
Project Start
2002-06-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$339,750
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Hu, Junping; Du, Jie; Zhang, Liping et al. (2010) XIAP reduces muscle proteolysis induced by CKD. J Am Soc Nephrol 21:1174-83
Wang, Xiaonan H; Zhang, Liping; Mitch, William E et al. (2010) Caspase-3 cleaves specific 19 S proteasome subunits in skeletal muscle stimulating proteasome activity. J Biol Chem 285:21249-57
Wang, Xiaonan H; Du, Jie; Klein, Janet D et al. (2009) Exercise ameliorates chronic kidney disease-induced defects in muscle protein metabolism and progenitor cell function. Kidney Int 76:751-9
Hu, Junping; Klein, Janet D; Du, Jie et al. (2008) Cardiac muscle protein catabolism in diabetes mellitus: activation of the ubiquitin-proteasome system by insulin deficiency. Endocrinology 149:5384-90
Hu, Zhaoyong; Lee, In Hee; Wang, Xiaonan et al. (2007) PTEN expression contributes to the regulation of muscle protein degradation in diabetes. Diabetes 56:2449-56
Zhou, Qiugen; Du, Jie; Hu, Zhaoyong et al. (2007) Evidence for adipose-muscle cross talk: opposing regulation of muscle proteolysis by adiponectin and Fatty acids. Endocrinology 148:5696-705
Cheng, Jizhong; Zhang, Jiqiang; Merched, Aksam et al. (2007) Mechanical stretch inhibits oxidized low density lipoprotein-induced apoptosis in vascular smooth muscle cells by up-regulating integrin alphavbeta3 and stablization of PINCH-1. J Biol Chem 282:34268-75
Cheng, Jizhong; Du, Jie (2007) Mechanical stretch simulates proliferation of venous smooth muscle cells through activation of the insulin-like growth factor-1 receptor. Arterioscler Thromb Vasc Biol 27:1744-51
Cheng, Jizhong; Cui, Ruwen; Chen, Chu-Huang et al. (2007) Oxidized low-density lipoprotein stimulates p53-dependent activation of proapoptotic Bax leading to apoptosis of differentiated endothelial progenitor cells. Endocrinology 148:2085-94
Workeneh, Biruh T; Rondon-Berrios, Helbert; Zhang, Liping et al. (2006) Development of a diagnostic method for detecting increased muscle protein degradation in patients with catabolic conditions. J Am Soc Nephrol 17:3233-9

Showing the most recent 10 out of 15 publications