6. ABSTRACT Pulmonary arterial hypertension (PAH) contributes to the morbidity and mortality of patients with lung and heart diseases, important health problems in the Veteran's population. Hypoxia induces PAH, which comprises structural remodeling of pulmonary arteries. Recently studies have found that mice deficient in Toll- like receptor 4 (TLR4) are susceptible to lethal oxidant lung injury and emphysema. Consistent with these observations that TLR4 deficiency is important in the development of lung diseases, we found that TLR4-, not TLR2-deficient mice spontaneously developed PAH. Further, hypoxia induced PAH in wild type and TLR2-/- mice, but did not enhance PAH spontaneously developed in TLR4-/- mice, suggesting that TLR4 plays an important role in maintaining normal pulmonary vasculature and hypoxia induces PAH via TLR4. This proposal is focused on understanding the role of TLR4 and its signaling pathways in regulating the development of PAH. Vascular remodeling represents a key step in the pathogenesis of PAH. At the cellular level, vascular remodeling is associated withincreased proliferation of smooth muscle cells (SMC). Preliminary studies found that hypoxia inhibited the expression of TLR4, and induced the expression of NOX1 and NOX4 in pulmonary artery SMC. On the other hand, SMC derived from TLR4-/- mice exhibited increased production of intracellular reactive oxygen species (ROS) and increased expression of NOX4 and NOX1. NOX4 is the predominant NADPH oxidase in SMC that produce ROS. Increased NOX4 promotes SMC proliferation, and inhibition of NOX4 reduces production of ROS and SMC proliferation. Therefore, we hypothesize that inhibition of TLR4 by hypoxia promotes PAH by activating NADPH oxidase signaling that increases SMC proliferation and vascular remodeling.
Two specific aims will be pursued to test the hypothesis:
Specific Aim 1 : Characterize the functional role of TLR4 signals in regulation of PAH in mice. The role of TLR4 expression, its functional domain and its adaptor protein, MyD88, in regulating the development of spontaneous and hypoxia-induced PAH will be characterized.
Specific Aim 2 : Delineate the molecular mechanisms responsible for TLR4 regulation of PAH. The cross talk between TLR4 signals and the NADPH oxidase-mediated redox signaling pathways in regulating SMC proliferation and vascular remodeling will be determined. Our studies will define an important novel function of TLR4 signaling in regulating SMC proliferation and vascular remodeling in the pathogenesis of PAH, which will broaden our knowledge on the crosstalk between innate immunity and oxidative stress signals in the pulmonary vasculature. Determination of the molecular mechanisms responsible for TLR signaling cascade in the pathogenesis of PAH might lead to novel strategies to prevent or intervene PAH, and possibly other diseases induced by chronic oxidative stress and vascular remodeling. Such disorders affect many veterans, the proposed studies will help to improve quality of their life.

Public Health Relevance

7. NARRATIVE: Pulmonary arterial hypertension (PAH) contributes to the morbidity and mortality of patients with lung and heart diseases, important health problems in the Veteran's population. We have found that mice deficient in toll like receptor 4 (TLR4) spontaneously developed PAH, that is associated with increased oxidative stress. This proposal will further define a novel function of TLR4 signaling in regulating vascular remodeling in the progression of PAH. The present studies will broaden our knowledge on the contribution of innate immunity to regulation of oxidative stress in the pulmonary vasculature, which will lead to development of novel therapeutics for prevention or treatment of PAH.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Respiration (PULM)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Birmingham VA Medical Center
United States
Zip Code
Su, Hairui; Sun, Chiao-Wang; Liu, Szu-Mam et al. (2018) Defining the epigenetic status of blood cells using a cyanine-based fluorescent probe for PRMT1. Blood Adv 2:2829-2836
Ma, Liping; Ambalavanan, Namasivayam; Liu, Hui et al. (2016) TLR4 regulates pulmonary vascular homeostasis and remodeling via redox signaling. Front Biosci (Landmark Ed) 21:397-409
Byon, Chang Hyun; Heath, Jack M; Chen, Yabing (2016) Redox signaling in cardiovascular pathophysiology: A focus on hydrogen peroxide and vascular smooth muscle cells. Redox Biol 9:244-253
Tran, Ngoc-Tung; Su, Hairui; Khodadadi-Jamayran, Alireza et al. (2016) The AS-RBM15 lncRNA enhances RBM15 protein translation during megakaryocyte differentiation. EMBO Rep 17:887-900
Byon, Chang Hyun; Chen, Yabing (2015) Molecular Mechanisms of Vascular Calcification in Chronic Kidney Disease: The Link between Bone and the Vasculature. Curr Osteoporos Rep 13:206-15
Deng, Liang; Huang, Lu; Sun, Yong et al. (2015) Inhibition of FOXO1/3 promotes vascular calcification. Arterioscler Thromb Vasc Biol 35:175-83
Heath, Jack M; Sun, Yong; Yuan, Kaiyu et al. (2014) Activation of AKT by O-linked N-acetylglucosamine induces vascular calcification in diabetes mellitus. Circ Res 114:1094-102
Sun, Yong; Byon, Chang Hyun; Yuan, Kaiyu et al. (2012) Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification. Circ Res 111:543-52
Chen, Jianfeng; Yuan, Kaiyu; Mao, Xia et al. (2012) Serum response factor regulates bone formation via IGF-1 and Runx2 signals. J Bone Miner Res 27:1659-68
Mao, Xia; Debenedittis, Paige; Sun, Yong et al. (2012) Vascular smooth muscle cell Smad4 gene is important for mouse vascular development. Arterioscler Thromb Vasc Biol 32:2171-7

Showing the most recent 10 out of 11 publications