Coronary artery disease is a major cause of mortality and disability in the United States and worldwide, and accounts for rising health costs. Clinically it is evident that plaque rupture, the most important cause of coronary thrombosis, is often associated with myocardial infarction and death. Many of the endogenous ligands that play a key role in plaque rupture are still not well understood. A variant of the extracellular matrix protein fibronectin containing the alternatively-spliced extra domain A (EDA+-FN) is absent in healthy arteries, but expressed in the atherosclerotic arteries of humans, suggesting a role in the pathophysiology of atherosclerosis. Our recent study using a specific inhibitor suggests that EDA+-FN aggravates ischemia/reperfusion brain injury via toll-like-receptor 4 (TLR4) pathway. Together these findings provide a compelling rationale to test the novel role of EDA+-FN and TLR4 signaling in modulating early and advanced atherosclerosis.
In Aim 1, we will test the hypothesis that EDA+-FN exacerbates early atherosclerosis via TLR4 signaling in apolipoprotein E-deficient (ApoE-/-) mice. Further, we will define the role of endothelial cell TLR4 in exacerbating early atherosclerosis.
In Aim 2, we will test the hypothesis that TLR4 signaling contributes to plaque vulnerability during advanced atherosclerosis in ApoE-/- mice. Further, we will test the hypothesis that EDA+-FN promotes plaque vulnerability via TLR4 signaling.
In Aim 3, we will define the role of endothelial cell EDA+-FN in atherosclerosis. As a preclinical approach, we will test the hypothesis that blocking EDA+-FN with monoclonal antibodies will inhibit atherosclerotic lesion progression in ApoE-/- mice. The proposed studies will use multidisciplinary innovative approaches, including several novel genetic mouse strains, and a novel intravital method to define the mechanisms by which EDA+-FN modulates atherosclerosis. The proposal is significant and may have important clinical implications because the studies designed herein will identify a novel endogenous ligand and unravel new pathway that modulate key atherogenic events in early and advance lesion development.

Public Health Relevance

The most common cause of coronary artery disease is the development of atherosclerotic plaques and their rupture, which is often associated with myocardial infarction and death. The proposed studies will determine the mechanistic role of extracellular matrix fibronectin extra domain A in exacerbating early atherosclerosis and promoting plaque vulnerability during advanced atherosclerosis. This research has the potential to identify a novel endogenous ligand and an underexplored pathway that could be targeted for prevention and treatment of the vulnerable plaques, thus enhancing human health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL118246-02
Application #
8666814
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Olive, Michelle
Project Start
2013-06-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Prakash, Prem; Nayak, Manasa K; Chauhan, Anil K (2016) P-selectin can promote thrombus propagation independently of both von Willebrand factor and thrombospondin1 in mice. J Thromb Haemost :
Dhanesha, Nirav; Prakash, Prem; Doddapattar, Prakash et al. (2016) Endothelial Cell-Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor-Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo-Inflammation. Arterioscler Thromb Vasc Biol 36:1829-37
Gu, Sean X; Blokhin, Ilya O; Wilson, Katina M et al. (2016) Protein methionine oxidation augments reperfusion injury in acute ischemic stroke. JCI Insight 1:
Niki, Masaru; Nayak, Manasa K; Jin, Hong et al. (2016) Dok-1 negatively regulates platelet integrin αIIbβ3 outside-in signalling and inhibits thrombosis in mice. Thromb Haemost 115:969-78
Dhanesha, Nirav; Ahmad, Ajmal; Prakash, Prem et al. (2015) Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation. Circulation 132:2237-47
Prakash, Prem; Kulkarni, Paresh P; Chauhan, Anil K (2015) Thrombospondin 1 requires von Willebrand factor to modulate arterial thrombosis in mice. Blood 125:399-406
Klutho, Paula J; Pennington, Steven M; Scott, Jason A et al. (2015) Deletion of Methionine Sulfoxide Reductase A Does Not Affect Atherothrombosis but Promotes Neointimal Hyperplasia and Extracellular Signal-Regulated Kinase 1/2 Signaling. Arterioscler Thromb Vasc Biol 35:2594-604
Doddapattar, Prakash; Gandhi, Chintan; Prakash, Prem et al. (2015) Fibronectin Splicing Variants Containing Extra Domain A Promote Atherosclerosis in Mice Through Toll-Like Receptor 4. Arterioscler Thromb Vasc Biol 35:2391-400
Prakash, Prem; Kulkarni, Paresh P; Lentz, Steven R et al. (2015) Cellular fibronectin containing extra domain A promotes arterial thrombosis in mice through platelet Toll-like receptor 4. Blood 125:3164-72
Jin, Hong; Gebska, Milena A; Blokhin, Ilya O et al. (2015) Endothelial PPAR-γ protects against vascular thrombosis by downregulating P-selectin expression. Arterioscler Thromb Vasc Biol 35:838-44

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