The overall goal of this proposal is to elucidate the mechanisms whereby scleroderma (systemic sclerosis, SSc) increases myocardial inflammation and fibrosis, which increases myocardial dysfunction (heart failure). Understanding the mechanisms by which this unique form of heart disease occurs may lead to the development of new therapies aimed at reducing morbidity and mortality in patients with SSc. The current proposal will test the hypothesis that matrix instability in SSc increases oxidative stress in the heart, which leads to increased production of angiostatic factors. Proinflammatory lipids such as oxidized phosphotidylcholine (ox-PC) are hypothesized to play a central role in the mechanisms by which SSc increases myocardial inflammation, fibrosis and eventually heart failure. This hypothesis is based on exciting preliminary data showing that D-4F, an apo A-I mimetic, essentially ablates myocardial inflammation and fibrosis in the tight skin (Tsk-/+) mouse, an established murine model of SSc.
In Aim 1, we will evaluate the role of matrix instability and the relationship between ox-PC, inflammation, fibrosis and heart function in the Tsk-/+ mouse. We will quantify ox-PC levels, nitric oxide (7NO) and superoxide anion (O27-) balance, cytokines, growth factors, angiostatin and endostatin levels.
In Aim 2, we will investigate the causal relationship between matrix instability and formation of ox-PC and myocardial inflammation, fibrosis, and heart failure in Tsk-/+ mice treated with D-4F, an ApoAl mimetic that was designed to improve high-density lipoprotein (HDL) function.
In Aim 3, we examine the mechanisms by which matrix instability, induced by defect fibrillin-1, activates cultured fibroblasts, endothelial cells and cardiac myocytes isolated from Tsk-/+ and C57BL/6 mice. As D-4F was sufficient to reduce myocardial inflammation and fibrosis in the Tsk-/+ mice, it is anticipated the D-4F treatments of the cells isolated from the Tsk-/+ and C57BL/6 mice will reveal the cellular mechanisms by which D-4F restores cellular function to improve myocardial function, reduce inflammation and fibrosis to decrease heart failure.

Public Health Relevance

This proposal systemically examines cellular mechanisms for how defects in matrix lead to production of angiostatic factors, oxidative stress and downstream events leading to inflammation, excess cytokine production, fibrosis and subsequent myocardial dysfunction and heart failure in systemic scleroderma. Based on preliminary data we will use an ApoAl mimetic, D-4F, to improve fibrosis, myocardial function and heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Wisconsin
Schools of Medicine
United States
Zip Code
Weihrauch, Dorothee; Krolikowski, John G; Jones, Deron W et al. (2017) Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice. J Vis Exp :
Weihrauch, Dorothee; Krolikowski, John G; Jones, Deron W et al. (2016) An IRF5 Decoy Peptide Reduces Myocardial Inflammation and Fibrosis and Improves Endothelial Cell Function in Tight-Skin Mice. PLoS One 11:e0151999
Zhang, Hao; Xu, Hao; Weihrauch, Dorothee et al. (2013) Inhibition of myeloperoxidase decreases vascular oxidative stress and increases vasodilatation in sickle cell disease mice. J Lipid Res 54:3009-15
Lohr, Nicole L; Ninomiya, James T; Warltier, David C et al. (2013) Far red/near infrared light treatment promotes femoral artery collateralization in the ischemic hindlimb. J Mol Cell Cardiol 62:36-42
Zhang, Hao; Jing, Xigang; Shi, Yang et al. (2013) N-acetyl lysyltyrosylcysteine amide inhibits myeloperoxidase, a novel tripeptide inhibitor. J Lipid Res 54:3016-29
Zaidi, Maria; Krolikowki, John G; Jones, Deron W et al. (2013) Transient repetitive exposure to low level light therapy enhances collateral blood vessel growth in the ischemic hindlimb of the tight skin mouse. Photochem Photobiol 89:709-13
Ninomiya, James T; Kuzma, Scott A; Schnettler, Timothy J et al. (2013) Metal ions activate vascular endothelial cells and increase lymphocyte chemotaxis and binding. J Orthop Res 31:1484-91
Xu, Hao; Krolikowski, John G; Jones, Deron W et al. (2012) 4F decreases IRF5 expression and activation in hearts of tight skin mice. PLoS One 7:e52046
Xu, Hao; Zaidi, Maria; Struve, Janine et al. (2011) Abnormal fibrillin-1 expression and chronic oxidative stress mediate endothelial mesenchymal transition in a murine model of systemic sclerosis. Am J Physiol Cell Physiol 300:C550-6
Nandedkar, S D; Weihrauch, D; Xu, H et al. (2011) D-4F, an apoA-1 mimetic, decreases airway hyperresponsiveness, inflammation, and oxidative stress in a murine model of asthma. J Lipid Res 52:499-508

Showing the most recent 10 out of 14 publications