Nitric oxide (NO)is generally considered to play a protective role in blood vessels. However, others and we have obtained evidence that this may not always be the case but the mechanisms underlying diverse responses to NO are not known. The purpose of this proposal is to test an exciting new hypothesis on the capacity of chronically elevated insulin levels to switch the role of nitric oxide from protective to deleterious substance in blood vessels. We have found that the inhibitory effects of NO on both motility and proliferation are abrogated in vascular smooth muscle cells chronically treated with insulin. These findings support a new hypothesis on the role of insulin as a switcher of vascular smooth muscle cell phenotypic responses to NO. Our preliminary results indicate that the motility-stimulatory effect of NO, uncovered by chronic insulin treatment of cultured rat aortic smooth muscle cells, is associated with increased PI 3 kinase activity and requires the functional availability of angiotensin II, of the adapter protein Gab1and the protein tyrosine phosphatase SHP2. Studies by others have found that Gab1 can be recruited to the plasma membrane via increased PIPS levels. However, the mechanistic linkage of chronic insulin treatment to Gab1 and SHP2 function has not been defined. Moreover, experiments to determine whether similar mechanisms may be applicable to abrogation of the antiproliferative effect of NO by chronic insulin treatment have not been performed. Finally, the pathophysiological significance of our results is unknown. We propose to implement the following specific aims:
Aim 1. To determine whether increased angiotensin II function is necessary and/or sufficient to account for the effect of insulin on PI3K activity and NO-induced cell motility.
Aim 2. To determine whether chronic insulin treatment recruits Gab1 to the cell membrane and whether insulin- independent recruitment of Gab1 or SHP2 to the cell membrane can mimic the motility-stimulatory effect of NO uncovered by chronic insulin treatment.
Aim 3 : To uncover mechanisms that describe how hyperinsulinemia attenuates the effect of NO as inhibitor of PDGF-induced DNA synthesis, in cultured rat aortic smooth muscle cells.
Aim 4. To determine whether expression of inducible nitric oxide synthase in vascular injury enhances neointima formation in hyperinsulinemic mice, but has the opposite effect in normoinsulinemic mice or in hyperinsulinemic mice treated with an AT1 receptor antagonist.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063886-08
Application #
7333236
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Goldman, Stephen
Project Start
2000-01-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
8
Fiscal Year
2008
Total Cost
$354,415
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Zhuang, Daming; Balani, Poonam; Pu, Qinghua et al. (2011) Suppression of PKG by PDGF or nitric oxide in differentiated aortic smooth muscle cells: obligatory role of protein tyrosine phosphatase 1B. Am J Physiol Heart Circ Physiol 300:H57-63
Pu, Qinghua; Zhuang, Daming; Thakran, Shalini et al. (2011) Mechanisms related to NO-induced motility in differentiated rat aortic smooth muscle cells. Am J Physiol Heart Circ Physiol 300:H101-8
Pu, Qinghua; Chang, Yingzi; Zhang, Chunxiang et al. (2009) Chronic insulin treatment suppresses PTP1B function, induces increased PDGF signaling, and amplifies neointima formation in the balloon-injured rat artery. Am J Physiol Heart Circ Physiol 296:H132-9
Xi, Qi; Adebiyi, Adebowale; Zhao, Guiling et al. (2008) IP3 constricts cerebral arteries via IP3 receptor-mediated TRPC3 channel activation and independently of sarcoplasmic reticulum Ca2+ release. Circ Res 102:1118-26
Zhuang, Daming; Pu, Qinghua; Ceacareanu, Bogdan et al. (2008) Chronic insulin treatment amplifies PDGF-induced motility in differentiated aortic smooth muscle cells by suppressing the expression and function of PTP1B. Am J Physiol Heart Circ Physiol 295:H163-73
Desai, Leena P; Sinclair, Scott E; Chapman, Kenneth E et al. (2007) High tidal volume mechanical ventilation with hyperoxia alters alveolar type II cell adhesion. Am J Physiol Lung Cell Mol Physiol 293:L769-78
Ceacareanu, Alice-Corina; Ceacareanu, Bogdan; Zhuang, Daming et al. (2006) Nitric oxide attenuates IGF-I-induced aortic smooth muscle cell motility by decreasing Rac1 activity: essential role of PTP-PEST and p130cas. Am J Physiol Cell Physiol 290:C1263-70
Chang, Yingzi; Ceacareanu, Bogdan; Zhuang, Daming et al. (2006) Counter-regulatory function of protein tyrosine phosphatase 1B in platelet-derived growth factor- or fibroblast growth factor-induced motility and proliferation of cultured smooth muscle cells and in neointima formation. Arterioscler Thromb Vasc Biol 26:501-7
Rafiq, Khadija; Kolpakov, Mikhail A; Abdelfettah, Malika et al. (2006) Role of protein-tyrosine phosphatase SHP2 in focal adhesion kinase down-regulation during neutrophil cathepsin G-induced cardiomyocytes anoikis. J Biol Chem 281:19781-92
Jagadeesha, D K; Lindley, Timothy E; Deleon, Jason et al. (2005) Tempol therapy attenuates medial smooth muscle cell apoptosis and neointima formation after balloon catheter injury in carotid artery of diabetic rats. Am J Physiol Heart Circ Physiol 289:H1047-53

Showing the most recent 10 out of 22 publications