Insulin resistance (IR) and hyperinsulinemia are important cardiovascular risk factors in diabetic patients. Insulin actions have been identified on endothelial cells (EC), vascular smooth muscle cells (VSMC) and macrophages. Yet, the question of whether insulin has pro- or anti-atherogenic actions has been hotly debated for many years. We propose that the acceleration of atherosclerosis in diabetes is due to selective insulin resistance in the vascular wall where hyperglycemia and elevated free fatty acids (FFA) can inhibit insulin signaling through the IRS/PI3K/Akt pathway. This may decrease insulin's anti-atherogenic actions in EC such as activation of eNOS, increased expression of heme oxygenase-1 and decreased expression of VCAM-1. Also, insulin and PKC activation may enhance the MAPK pathway leading to increased expression of pro- atherogenic activities such as ET-1, PAI-1 expression, migration and proliferation of VSMC, creating "selective" insulin resistance in the vessel wall. In this grant period, we showed that deletion of insulin receptors, specifically in EC, accelerated atherosclerosis due to the loss of novel insulin actions to decrease VCAM-1 expression. We also showed that hyperinsulinemia alone, without vascular or systemic IR, did not accelerate atherosclerosis in ApoE-/- mice. We have shown that one cause of selective insulin resistance in the endothelium is due to the activation of PKC, especially of the a and b isoforms, induced by hyperglycemia and elevated FFA. We also identified the targets of PKCb activation induced by angiotensin on insulin signaling molecules including p-Ser303 in IRS2 and p-Thr86 of p85a/PI3K. The overexpression of PKCb isoform, specifically in EC, selectively inhibited insulin signaling through the IRS/Akt pathway and exacerbated atherosclerosis. Thus, we propose to: 1. Characterize the effect of exogenous insulin treatment and PKCb inhibition on the development of atherosclerosis in a new model of ApoE-/- mice, which exhibit hyperinsulinemia, hyperglycemia, hypercholesterolemia and IR at the vessel wall, and systemically by feeding a high fat diet (HFD, 60% fat) instead of a western diet (WD, 42% fat), providing a simple diet induced model with atherosclerosis that mimics all of the metabolic abnormalities of type 2 diabetes. 2a. Evaluate ApoE-/- mice overexpressing IRS1 specifically in the endothelium, EIRS1/ApoE-/- mice, which showed dramatic decreases in atherosclerosis, and possibly identified a novel pathway by which insulin activates eNOS via increases in endothelin B receptor (ETB) expression by a pathway independent of p-S(1176)eNOS. 2b. Determine whether intimal hyperplasia and atherosclerosis will decrease in mice which are expressing S-A(1176)eNOS and overexpressing IRS1 in EC on ApoE-/- background while on HFD. 3. We will address the question of insulin's potential atherogenic effects on VSMC by determining the role of insulin and its receptor on aortic SMC regarding their impact on atherosclerotic lesions in ApoE-/- mice with deletion of insulin receptor on HFD.

Public Health Relevance

Our goal is to identify the role of insulin on the development of atherosclerosis by understanding its actions on endothelial cells and arterial smooth muscle cells. By deleting or overexpressing insulin receptors in these cells, we began to clarify how insulin may have both anti- and pro-atherogenic actions. We have also developed new mouse models of atherosclerosis mimicking T2DM as well as discovering new ways by which insulin could activate eNOS, a potent regulator of vascular function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK053105-14
Application #
8697558
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Jones, Teresa L Z
Project Start
1997-09-15
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
14
Fiscal Year
2014
Total Cost
$368,887
Indirect Cost
$146,387
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Rask-Madsen, Christian; King, George L (2013) Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab 17:20-33
Park, Kyoungmin; Li, Qian; Rask-Madsen, Christian et al. (2013) Serine phosphorylation sites on IRS2 activated by angiotensin II and protein kinase C to induce selective insulin resistance in endothelial cells. Mol Cell Biol 33:3227-41
Li, Qian; Park, Kyoungmin; Li, Chenzhong et al. (2013) Induction of vascular insulin resistance and endothelin-1 expression and acceleration of atherosclerosis by the overexpression of protein kinase C-* isoform in the endothelium. Circ Res 113:418-27
Maeno, Yasuhiro; Li, Qian; Park, Kyoungmin et al. (2012) Inhibition of insulin signaling in endothelial cells by protein kinase C-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase (PI3K). J Biol Chem 287:4518-30
Rask-Madsen, Christian; Buonomo, Erica; Li, Qian et al. (2012) Hyperinsulinemia does not change atherosclerosis development in apolipoprotein E null mice. Arterioscler Thromb Vasc Biol 32:1124-31
Mima, Akira; Ohshiro, Yuzuru; Kitada, Munehiro et al. (2011) Glomerular-specific protein kinase C-*-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity. Kidney Int 79:883-96
Rask-Madsen, Christian; King, George L (2011) Endothelium-dependent delivery of insulin to muscle interstitium. Cell Metab 13:236-8
Rask-Madsen, Christian; Li, Qian; Freund, Bryn et al. (2010) Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab 11:379-89
Isshiki, Keiji; He, Zhiheng; Maeno, Yasuhiro et al. (2008) Insulin regulates SOCS2 expression and the mitogenic effect of IGF-1 in mesangial cells. Kidney Int 74:1434-43
Geraldes, Pedro; Yagi, Kunimasa; Ohshiro, Yuzuru et al. (2008) Selective regulation of heme oxygenase-1 expression and function by insulin through IRS1/phosphoinositide 3-kinase/Akt-2 pathway. J Biol Chem 283:34327-36

Showing the most recent 10 out of 33 publications