Morbidity and mortality secondary to cardiovascular disease is the major health problem in obese patients. Obese patients are burdened with an array of metabolic dysfunctions associated with excess weight. Most notable of these is insulin resistance which causes deleterious changes in plasma chemistry, compensatory over-production of insulin and eventual failure of the pancreatic 2-cell and Type 2 diabetes. Because obese patients present with both metabolic and cardiovascular dysfunction, it is widely suspected that the two are dependent variables. The extent to which this is true and the mechanisms linking metabolic and cardiovascular disease are unknown. In preliminary data for this application, we have generated a novel mouse model in which an insulin receptor desensitizing gene, protein tyrosine phosphatase 1B (PTP1B) is deleted from obese mice. The result is a mouse with persistent obesity and correction of peripheral insulin resistance. Obese mice show impairment of microvascular endothelial NO-mediated vasodilation in vitro, a defect corrected by PTP1B deletion. This suggests that insulin resistance is the causal aspect of obesity-induced metabolic dysfunction. The molecular mechanisms underlying these microvascular defects will be determined in Aim 1. The cardiovascular impact of correcting insulin resistance in obese mice will be determined in Aim 2, using blood flow, blood pressure and vascular remodeling as endpoints. While preliminary data provides novel evidence that insulin resistance and cardiovascular dysfunction are linked, the nature of this relationship is unclear. High levels of HbA1c in obese mice suggest an environment favorable to non-enzymatic glycation and this association is strengthened by the increased expression of the Receptor for Advanced Glycation End-products (RAGE). Both deficits are corrected in obese PTP1B null mice with improved insulin resistance. This leads us to the hypothesis that RAGE is the mechanistic link between insulin resistance and cardiovascular dysfunction and this hypothesis will be tested in Aim 3 by the generation of novel dual KO mice, obese mice lacking RAGE. Taken together, these studies will generate new information about the mechanisms, mediators and physiologic impact of obesity-induced metabolic dysfunction. Successful completion of these aims may identify new targets to aid in the treatment of the most common clinical outcomes of obesity.

Public Health Relevance

Cardiovascular disease is the greatest health threat in the obese population, in part due to the metabolic dysfunction that accompanies obesity. Studies proposed in the application identify two new therapeutic targets, PTP1B and RAGE, that may uncouple the deleterious relationship between obesity and cardiovascular disease by breaking the """"""""metabolic connection"""""""". Completion of these experiments will not only potentially validate these new targets but also better clarify why obesity causes cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL092446-01A1
Application #
7589431
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Ershow, Abby
Project Start
2009-01-01
Project End
2013-11-30
Budget Start
2009-01-01
Budget End
2009-11-30
Support Year
1
Fiscal Year
2009
Total Cost
$441,000
Indirect Cost
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Chen, F; Wang, Y; Rafikov, R et al. (2017) RhoA S-nitrosylation as a regulatory mechanism influencing endothelial barrier function in response to G+-bacterial toxins. Biochem Pharmacol 127:34-45
Chen, Feng; Haigh, Steven; Yu, Yanfang et al. (2015) Nox5 stability and superoxide production is regulated by C-terminal binding of Hsp90 and CO-chaperones. Free Radic Biol Med 89:793-805
Nernpermpisooth, Nitirut; Qiu, Shuiqing; Mintz, James D et al. (2015) Obesity alters the peripheral circadian clock in the aorta and microcirculation. Microcirculation 22:257-66
Czikora, Istvan; Feher, Attila; Lucas, Rudolf et al. (2015) Caveolin-1 prevents sustained angiotensin II-induced resistance artery constriction and obesity-induced high blood pressure. Am J Physiol Heart Circ Physiol 308:H376-85
Chen, Feng; Kumar, Sanjiv; Yu, Yanfang et al. (2014) PKC-dependent phosphorylation of eNOS at T495 regulates eNOS coupling and endothelial barrier function in response to G+ -toxins. PLoS One 9:e99823
Chen, Feng; Barman, Scott; Yu, Yanfang et al. (2014) Caveolin-1 is a negative regulator of NADPH oxidase-derived reactive oxygen species. Free Radic Biol Med 73:201-13
Wang, Yusi; Chen, Feng; Le, Brian et al. (2014) Impact of Nox5 polymorphisms on basal and stimulus-dependent ROS generation. PLoS One 9:e100102
Qiu, Shuiqing; Mintz, James D; Salet, Christina D et al. (2014) Increasing muscle mass improves vascular function in obese (db/db) mice. J Am Heart Assoc 3:e000854
Chatterjee, Tapan K; Basford, Joshua E; Yiew, Kan Hui et al. (2014) Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease. Adipocyte 3:333-8
Barman, Scott A; Chen, Feng; Su, Yunchao et al. (2014) NADPH oxidase 4 is expressed in pulmonary artery adventitia and contributes to hypertensive vascular remodeling. Arterioscler Thromb Vasc Biol 34:1704-15

Showing the most recent 10 out of 42 publications