The transition to a dysfunction endothelial cell phenotype is regulated by multiple environmental factors, including both systemic risk factors (ex. oxidized LDL) and local blood flow patterns. My research suggests that local matrix composition is a novel regulator of endothelial cell dysfunction. Transitional matrix proteins (ex. fibronectin) accumulate in the subendothelial matrix early during atherogenesis and prime endothelial cells for dysfunction by enhancing flow-induced permeability and proinflammatory gene expression. In contrast, basement membrane proteins limit endothelial cell dysfunction. Multiple atherogenic stimuli, including disturbed flow and oxidized LDL, activate the Rac/cdc42 effector p21 activated kinase (PAK), and PAK inhibitors reduce endothelial permeability and proinflammatory responses both in vitro and at atherosclerosis- prone sites in vivo. Despite activation of upstream pathways, basement membrane proteins do not support PAK activation, suggesting that signals from the basement membrane inhibit PAK to limit endothelial cell dysfunction. As such, PAK activation in vivo is restricted to regions of transitional matrix deposition. Protein kinase A (PKA) phosphorylates and inhibits PAK in cells in suspension. In addition, PKA reduces both proinflammatory gene expression and endothelial permeability, suggesting PKA is a good candidate for matrix- specific PAK suppression. Preliminary data show that basement membrane proteins enhance flow-induced PKA activation, and inhibiting PKA in cells on basement membrane proteins is sufficient to restore flow- induced PAK activation and proinflammatory responses. These data lead us to hypothesize that basement membrane proteins utilize a PKA-dependent signal to inhibit PAK and limit endothelial cell dysfunction, whereas transitional matrix deposition primes endothelial cells to progress to a dysfunctional phenotype. The proposed work will test this hypothesis by determining the mechanisms by which matrix signaling modulates PKA activation (Aim 1) and by exploring the molecular mechanisms of PKA-dependent PAK inhibition (Aim 2). To illustrate the broad scope of this novel signaling axis across multiple atherogenic signals, we will determine how matrix composition and signaling through the PKA and PAK pathways affect oxidized LDL-induced endothelial cell dysfunction (Aim 3). This work will utilize a multifactorial approach to provide insight into the role of the endogenous basement membrane as a novel atheroprotective agent.
Atherosclerosis, a chronic inflammatory disease of the vessel wall, is the leading cause of death in developed countries. Our research suggests that changes in the local extracellular matrix may serve as a form of tissue memory. Normal components of the tissue matrix limit cellular responsiveness to transient injurious stimuli, while transitional matrix deposition in response to chronic stimuli enhances cellular responsiveness to propagate tissue remodeling. Understanding the molecular mechanisms by which matrix composition affects cell physiology could provide novel therapeutic targets to limit chronic inflammatory diseases, such as atherosclerosis and arthritis.
|Mravic, Marco; Hu, Hailin; Lu, Zhenwei et al. (2018) De novo designed transmembrane peptides activating the ?5?1 integrin. Protein Eng Des Sel 31:181-190|
|Janjanam, Jagadeesh; Zhang, Baolin; Mani, Arul M et al. (2018) LIM and cysteine-rich domains 1 is required for thrombin-induced smooth muscle cell proliferation and promotes atherogenesis. J Biol Chem 293:3088-3103|
|Vozenilek, Aimee E; Navratil, Aaron R; Green, Jonette M et al. (2018) Macrophage-Associated Lipin-1 Enzymatic Activity Contributes to Modified Low-Density Lipoprotein-Induced Proinflammatory Signaling and Atherosclerosis. Arterioscler Thromb Vasc Biol 38:324-334|
|Shrestha, Bandana; Prasai, Priya K; Kaskas, Amir M et al. (2018) Differential arterial and venous endothelial redox responses to oxidative stress. Microcirculation 25:e12486|
|Prasai, Priya K; Shrestha, Bandana; Orr, A Wayne et al. (2018) Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cells. Redox Biol 19:22-27|
|Al-Yafeai, Zaki; Yurdagul Jr, Arif; Peretik, Jonette M et al. (2018) Endothelial FN (Fibronectin) Deposition by ?5?1 Integrins Drives Atherogenic Inflammation. Arterioscler Thromb Vasc Biol 38:2601-2614|
|Alam, Shafiul; Abdullah, Chowdhury S; Aishwarya, Richa et al. (2018) Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation-Induced Cardiac Proteotoxicity. J Am Heart Assoc 7:|
|Chandra, Mini; Escalante-Alcalde, Diana; Bhuiyan, Md Shenuarin et al. (2018) Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure. Redox Biol 14:261-271|
|Finney, Alexandra C; Funk, Steven D; Green, Jonette M et al. (2017) EphA2 Expression Regulates Inflammation and Fibroproliferative Remodeling in Atherosclerosis. Circulation 136:566-582|
|Alam, Shafiul; Abdullah, Chowdhury S; Aishwarya, Richa et al. (2017) Sigmar1 regulates endoplasmic reticulum stress-induced C/EBP-homologous protein expression in cardiomyocytes. Biosci Rep 37:|
Showing the most recent 10 out of 29 publications