Hyperhomocysteinemia (HHcy) is an important non-lipid risk factor for cardiovascular disease (CVD). At present, our mechanistic knowledge of HHcy's correlation with dyslipidemia and the development of atherosclerosis is limited. Notwithstanding, it has been suggested that HHcy affects hepatic lipid metabolism, thereby contributing to fatty liver, a condition described in humans and animals with HHcy. Our previous findings suggested that plasma HHcy levels are significant negative correlated with plasma HDL-C and apolipoprotein AI (apoA-I), a predominant structural protein in HDL particles and cofactor for HDL maturation, in patients with coronary heart disease (CHD) and in atherosclerosis mice. We also found that severe HHcy is associated with increased HDL-C turnover and increased protein levels of hepatic/vascular endothelial lipase (EL), an HDL degradation enzyme in mice. Because the mechanistic link between HHcy and HDL dysfunction has never been studied, we plan to investigate the role and mechanism of HHcy-induced HDL dysfunction in our newly established severe HHcy models with double gene deficiency for Cystathionine ?-synthase (CBS) which degrade homocysteine (Hcy), and either apolipoprotein E (ApoE) or low density lipoprotein receptor (LDLR), and with an inducible human CBS gene (Tg-hCBS ApoE-/- Cbs-/-, Tg- hCBS Cbs-/-, and Ldlr-/- Cbs-/+). These set of transgenic mice can circumvent the potential limitations of different model system and are valid for assessing the role and mechanistic links of HHcy-HDL metabolism with/without hyperlipidemia and with/without apoE deficiency. The central hypothesis to be tested in this proposal is that HHcy causes ApoA1 reduction and EL activation, resulting in reduced HDL maturation and increased HDL degradation, leading to impaired reverse cholesterol transport (RCT) contributing to the development of atherosclerosis. We proposed in Aim 1 to determine the effect of HHcy on HDL biosynthesis, catabolism, and function in our newly three developed HHcy models, in Aim 2 to identify molecular targets and underlying biochemical basis mediating HHcy-altered HDL metabolism, and in Aim 3 to reverse HHcy, ApoA1 deficiency or EL activation, and to examine the effect on HDL-raising/function and atherosclerosis. The goal of this proposal is to investigate the role of HHcy in HDL metabolism, in the hope to identify the underlying molecular mechanisms and novel therapies. If the key steps in Hcy-induced dyslipidemia and atherosclerosis can be identified, new genetic or pharmacological therapeutic targets can be utilized for treatment.
Hyperhomocysteinemia (HHcy) has been identified as a potent risk factor for cardiovascular disease (CVD). However the underlying mechanism remains largely unclear. This hampered the development of effective medical therapies. Recent studies from our group have identified that HHcy inhibit HDL biosynthesis and its function in human and in mice. This proposal seeks to develop a detailed understanding of this regulation with the goal to identify key molecules responsible for HHcy-induced HDL dysfunction and molecular targets for HDL therapy in CVD.
|Fang, Pu; Li, Xinyuan; Dai, Jin et al. (2018) Immune cell subset differentiation and tissue inflammation. J Hematol Oncol 11:97|
|Li, Xinyuan; Wang, Luqiao; Fang, Pu et al. (2018) Lysophospholipids induce innate immune transdifferentiation of endothelial cells, resulting in prolonged endothelial activation. J Biol Chem 293:11033-11045|
|Xu, Yanjie; Xia, Jixiang; Liu, Suxuan et al. (2017) Endocytosis and membrane receptor internalization: implication of F-BAR protein Carom. Front Biosci (Landmark Ed) 22:1439-1457|
|Dai, Jin; Fang, Pu; Saredy, Jason et al. (2017) Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40+ monocyte differentiation. J Hematol Oncol 10:141|
|Yang, Jiyeon; Fang, Pu; Yu, Daohai et al. (2016) Chronic Kidney Disease Induces Inflammatory CD40+ Monocyte Differentiation via Homocysteine Elevation and DNA Hypomethylation. Circ Res 119:1226-1241|
|Mai, Jietang; Nanayakkara, Gayani; Lopez-Pastrana, Jahaira et al. (2016) Interleukin-17A Promotes Aortic Endothelial Cell Activation via Transcriptionally and Post-translationally Activating p38 Mitogen-activated Protein Kinase (MAPK) Pathway. J Biol Chem 291:4939-54|
|Xi, Hang; Zhang, Yuling; Xu, Yanjie et al. (2016) Caspase-1 Inflammasome Activation Mediates Homocysteine-Induced Pyrop-Apoptosis in Endothelial Cells. Circ Res 118:1525-39|
|Liu, Suxuan; Xiong, Xinyu; Thomas, Sam Varghese et al. (2016) Analysis for Carom complex, signaling and function by database mining. Front Biosci (Landmark Ed) 21:856-72|
|Sha, Xiaojin; Meng, Shu; Li, Xinyuan et al. (2015) Interleukin-35 Inhibits Endothelial Cell Activation by Suppressing MAPK-AP-1 Pathway. J Biol Chem 290:19307-18|
|Nelson, Jun; Wu, Yi; Jiang, Xiaohua et al. (2015) Hyperhomocysteinemia suppresses bone marrow CD34+/VEGF receptor 2+ cells and inhibits progenitor cell mobilization and homing to injured vasculature-a role of ?1-integrin in progenitor cell migration and adhesion. FASEB J 29:3085-99|
Showing the most recent 10 out of 38 publications