The role of growth factors such as insulin-like growth factor-1 (IGF-1) in atherogenesis is often thought to be permissive, but results from our current grant cycle indicate that IGF-1 has anti-inflammatory, anti-oxidant and anti-atherosclerotic effects. When targeted to smooth muscle cells (SMC), IGF-1 overexpression alters atherosclerotic plaque composition, increasing plaque SMC and collagen content and reducing necrotic cores. These findings suggest that IGF-1 increases plaque stability, which could be very important clinically, since most acute cardiovascular events result from plaque instability, erosion and rupture, rather than changes in plaque burden. The long-term objective of this project is to understand how IGF-1 alters atherosclerotic plaque biology and we will achieve this through two specific aims:
Specific Aim 1. Demonstrate that IGF-1-induced atheroprotection is mediated in large part via IGF-1's effect on monocytes/macrophages and investigate mechanisms. We have generated 3 novel mouse models that overexpress IGF-1 constitutively or inducibly in the monocyte/macrophage lineage or in which monocyte/macrophage IGF-1 receptor is deleted. We will use these models to demonstrate that monocyte/macrophage IGF-1 has anti-inflammatory and anti- atherogenic effects and suppresses monocyte chemotaxis, monocyte recruitment and adhesion to endothelium, macrophage lipid accumulation, macrophage oxidative stress/apoptosis, foam cell formation and atherosclerotic plaque development. We will examine mechanisms whereby IGF-1 exerts these effects and in particular the roles of chemokine receptors (CCR1, CCR2) and of 12/15-lipoxygenase and lipoprotein lipase.
Specific Aim 2 : To demonstrate that IGF-1 increases atherosclerotic plaque stability and determine mechanisms. We will use IGF-1 infusion and SMC targeted IGF-1 transgenic mice and IGF-1 receptor null mice to examine whether effects of IGF-1 on plaque composition, contractile protein and collagen expression are mediated via endocrine and/or autocrine/paracrine mechanisms and whether they translate into a reduced frequency of plaque disruption in the brachiocephalic artery. We will also analyze the role of monocyte/macrophage IGF-1 in these processes. To further understand mechanisms whereby IGF-1 enhances plaque stability we will examine IGF-1 induction of collagen synthesis and assembly in vitro and the involvement of 1221- and 1521-integrins and test potential cross-talk between IGF-1R and 1221 integrin signaling leading to cell cycle suppression and enhanced contractile marker expression. Our results should provide important insights into mechanisms whereby IGF-1, acting on monocytes/macrophages and SMC, alters plaque biology and reduces plaque disruptions. These findings should allow development of innovative therapies targeted at reducing acute vascular events that are most often related to plaque instability.

Public Health Relevance

Most acute cardiovascular events such as heart attacks are caused by disruption of atherosclerotic plaques which have become unstable. We propose to use a growth factor called IGF-1 to reduce the size and alter the composition of these plaques in animals, making them less inflammatory and more stable. If applied to humans this strategy could be a breakthrough that reduces the incidence of acute cardiovascular events.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070241-11
Application #
8575338
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Ershow, Abby
Project Start
2002-04-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
11
Fiscal Year
2014
Total Cost
$338,625
Indirect Cost
$113,625
Name
Tulane University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Kim, Seong Chul; Boese, Austin C; Moore, Matthew H et al. (2018) Rapid estrogen receptor-? signaling mediated by ERK activation regulates vascular tone in male and ovary-intact female mice. Am J Physiol Heart Circ Physiol 314:H330-H342
Sukhanov, Sergiy; Higashi, Yusuke; Shai, Shaw-Yung et al. (2018) SM22? (Smooth Muscle Protein 22-?) Promoter-Driven IGF1R (Insulin-Like Growth Factor 1 Receptor) Deficiency Promotes Atherosclerosis. Arterioscler Thromb Vasc Biol 38:2306-2317
Hou, Xuwei; Snarski, Patricia; Higashi, Yusuke et al. (2017) Nuclear complex of glyceraldehyde-3-phosphate dehydrogenase and DNA repair enzyme apurinic/apyrimidinic endonuclease I protect smooth muscle cells against oxidant-induced cell death. FASEB J 31:3179-3192
Yoshida, Tadashi; Delafontaine, Patrice (2016) An Intronic Enhancer Element Regulates Angiotensin II Type 2 Receptor Expression during Satellite Cell Differentiation, and Its Activity Is Suppressed in Congestive Heart Failure. J Biol Chem 291:25578-25590
Higashi, Yusuke; Sukhanov, Sergiy; Shai, Shaw-Yung et al. (2016) Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E-Deficient Mice. Circulation 133:2263-78
Sakamuri, Siva S V P; Valente, Anthony J; Siddesha, Jalahalli M et al. (2016) TRAF3IP2 mediates aldosterone/salt-induced cardiac hypertrophy and fibrosis. Mol Cell Endocrinol 429:84-92
Somanna, Naveen K; Valente, Anthony J; Krenz, Maike et al. (2016) The Nox1/4 Dual Inhibitor GKT137831 or Nox4 Knockdown Inhibits Angiotensin-II-Induced Adult Mouse Cardiac Fibroblast Proliferation and Migration. AT1 Physically Associates With Nox4. J Cell Physiol 231:1130-41
Delafontaine, Patrice; Yoshida, Tadashi (2016) THE RENIN-ANGIOTENSIN SYSTEM AND THE BIOLOGY OF SKELETAL MUSCLE: MECHANISMS OF MUSCLE WASTING IN CHRONIC DISEASE STATES. Trans Am Clin Climatol Assoc 127:245-258
Sakamuri, Siva Sankara Vara Prasad; Higashi, Yusuke; Sukhanov, Sergiy et al. (2016) TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE(-/-) mice. Atherosclerosis 252:153-160
Sukhanov, Sergiy; Snarski, Patricia; Vaughn, Charlotte et al. (2015) Insulin-like growth factor I reduces lipid oxidation and foam cell formation via downregulation of 12/15-lipoxygenase. Atherosclerosis 238:313-20

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