Overall aim of this grant application is to elucidate the causal relationship between endothelial dysfunction, oxidative stress, and the inflammatory cytokine, tumor necrosis factor alpha (TNF-(). Accordingly, this proposal will test the hypothesis that inflammation produces endothelial dysfunction in Type II diabetes, which is a leading risk factor for coronary heart disease. There are three aims, and associated with each of the aims are three or four hypotheses.
The first aim will determine if TNF-( plays a critical role in diabetic endothelial dysfunction. We propose that: 1). In dbTNF-/dbTNF- mice endothelial dilation will be greater than that in diabetic (db/db) mice, and comparable to Db/db controls. Decrements in endothelial function in db/db mice will progressively increase from 6 to 12 to 18 weeks. 2). Administration of neutralizing antibodies to TNF-( will ameliorate endothelial dysfunction in db/db mice of varying ages, 6, 12 and 18 weeks. The effect will be most prominent in the older animals. 3). Expression of TNF-( and TNF-( receptors (TNFRs: TNFR1 and TNFR2) are elevated in coronary arterioles, even at the age of 6 weeks before the development of diabetes, in db/db mice compared to Db/db mice. We propose that the expression of TNF-( and its receptors increase progressively with age, and with the development of diabetes.
The second aim will determine if TNF-( produces endothelial dysfunction by stimulation of the production of reactive oxygen species (ROS) in db/db mice through activation of NADPH oxidase. We propose to test anti-TNF-( attenuates ROS production in diabetes in db/db mice.
The third aim will determine if AGE/RAGE and TNF-( signaling interact to amplify the oxidative stress and induce endothelial dysfunction in diabetic mice. We propose to test if: 1). In dbTNF-/dbTNF- mice, RAGE expression and AGE formation are less than in db/db mice. 2). Activation of the transcription factor NFkB is less in dbTNF-/dbTNF- or db/db + sRAGE mice compared to db/db mice. 3). In db/db mice of varying ages: 6, 12 and 18 weeks, sRAGE restores endothelial dependent dilation toward that of Db/db controls by reducing TNF-( expression and ROS production. 4). Activation of RAGE compromises endothelial dilation to a greater extent in db/db than in Db/db or dbTNF-/dbTNF- mice. 5). In db/db mice, sRAGE reduces ROS production and TNF-( expression compared to that in db/db mice, and this effect will be mediated through decreased expression of NAD(P)H oxidases. We utilize a combination of approaches involving diameter measurements of isolated coronary arterioles from mouse heart, the oxidative fluorescent dye dihydroethidium (DHE-fluorescence imaging) and electron paramagnetic resonance (EPR) to evaluate O2.- production, electrochemical detection of authentic NO, real time PCR of RNA transcripts, and Western Blotting to evaluate expression of key proteins in Db/db control, dbTNF-/dbTNF-, db/db + sRAGE and db/db mice. We believe that this study will provide a solution to the specific problem and new approaches for the longer term; it might represent exciting new targets for the development of drugs for cardiovascular disorders in ischemic heart disease, obesity, diabetes and hypertension. ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Rabadan-Diehl, Cristina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Texas A&M University
Veterinary Sciences
Schools of Veterinary Medicine
College Station
United States
Zip Code
Jia, Guanghong; Hill, Michael A; Sowers, James R (2018) Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circ Res 122:624-638
Jia, Guanghong; Habibi, Javad; Aroor, Annayya R et al. (2018) Enhanced endothelium epithelial sodium channel signaling prompts left ventricular diastolic dysfunction in obese female mice. Metabolism 78:69-79
Jia, Guanghong; Aroor, Annayya R; Hill, Michael A et al. (2018) Role of Renin-Angiotensin-Aldosterone System Activation in Promoting Cardiovascular Fibrosis and Stiffness. Hypertension 72:537-548
Jia, Guanghong; Habibi, Javad; Aroor, Annayya R et al. (2018) Epithelial Sodium Channel in Aldosterone-Induced Endothelium Stiffness and Aortic Dysfunction. Hypertension 72:731-738
Qiu, Tianyi; Li, Min; Tanner, Miles A et al. (2018) Depletion of dendritic cells in perivascular adipose tissue improves arterial relaxation responses in type 2 diabetic mice. Metabolism 85:76-89
Dhar, Srijita; Sun, Zhe; Meininger, Gerald A et al. (2017) Nonenzymatic glycation interferes with fibronectin-integrin interactions in vascular smooth muscle cells. Microcirculation 24:
Hong, Kwangseok; Lee, Sewon; Li, Rong et al. (2016) Adiponectin Receptor Agonist, AdipoRon, Causes Vasorelaxation Predominantly Via a Direct Smooth Muscle Action. Microcirculation 23:207-20
Lee, Sewon; Yang, Yan; Tanner, Miles A et al. (2015) Heterogeneity in Kv7 channel function in the cerebral and coronary circulation. Microcirculation 22:109-121
Chen, Xiuping; Zhang, Hanrui; Hill, Michael A et al. (2015) Regulation of Coronary Endothelial Function by Interactions between TNF-?, LOX-1 and Adiponectin in Apolipoprotein E Knockout Mice. J Vasc Res 52:372-82
Scallan, Joshua P; Hill, Michael A; Davis, Michael J (2015) Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling. Cardiovasc Res 107:89-97

Showing the most recent 10 out of 52 publications