Percutaneous coronary intervention (PCI) is the mainstay treatment to unblock atherosclerotic arteries. Despite significant technological advances in PCI, restenosis (re-narrowing) secondary to neointimal hyperplasia remains an important cause of morbidity and death. The extent of local and systemic inflammation after PCI highly correlates with the extent of restenosis. The integrin Mac-1 (also known as CD11b/CD18, CR3, and ?M?2), which is primarily expressed on leukocytes, plays a key role in vascular injury and inflammation. Mac-1 mediates leukocyte adhesion, migration, and recruitment after vascular injury. As approaches using anti-Mac-1 blockers have had limited success in human clinical trials, in this project, we propose an alternative innovative approach for treating vascular injury by activating instead of blocking Mac-1 with a novel class of compounds that we have termed leukadherins. We demonstrate the surprising discovery that leukadherins significantly promote endothelial re-growth and prevent neointimal hyperplasia after arterial balloon injury in rats. Our overall hypothesis is that activation of the Mac-1 receptor via leukadherins is sufficient to prevent leukocyte transmigration and activation, decreasing vascular inflammation and neointima formation. We also hypothesize that leukadherin suppress the inflammatory activation of leukocytes during the repair of the injured vasculature. We propose three Specific Aims (SA) to test our hypotheses. In SA1, we will search for molecular connections between Mac-1 activation and leukocyte deactivation after vascular injury. We will investigate the role of inflammation suppressors Akt and Syk on leukadherin's anti-inflammatory effects. In SA2, we will identify the in vivo mechanism by which leukadherins promote endothelial recovery. We will assess how leukadherins promote local endothelial cell growth over endothelial progenitor cell recruitment to accelerate vascular re- endothelialization. Finally, in SA3 we will identify the in vivo mechanisms by which leukadherins reduce neointimal hyperplasia in a clinically relevant model of in-stent restenosis. We will compare our lead leukadherin agonist, LA1, with M1/70 mAb (antagonist) in a rabbit model of in-stent restenosis, and will provide a basis for progressing to preclinical studies in larger animals (pigs) and, eventually, to clinical trials.
Restenosis is the major complication after coronary interventions, accounting for $3 billion dollars in medical expenditures annually in the US alone. In this study, we will help define whether and how pharmacologic activation of integrin Mac-1 has therapeutic potential for the prevention of restenosis. This will pave the way for the future discovery of novel therapeutic agents to treat restenosis after PCI as well as other vascular inflammatory diseases.
|Faridi, Mohd Hafeez; Khan, Samia Q; Zhao, Wenpu et al. (2017) CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus. J Clin Invest 127:1271-1283|
|Lee, Ha Won; Khan, Samia Q; Khaliqdina, Shehryar et al. (2017) Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1. J Biol Chem 292:732-747|
|Johnson, Courtney M; O'Brien, Xian M; Byrd, Angel S et al. (2017) Integrin Cross-Talk Regulates the Human Neutrophil Response to Fungal ?-Glucan in the Context of the Extracellular Matrix: A Prominent Role for VLA3 in the Antifungal Response. J Immunol 198:318-334|
|Lee, Ha Won; Khan, Samia Q; Faridi, Mohd Hafeez et al. (2015) A Podocyte-Based Automated Screening Assay Identifies Protective Small Molecules. J Am Soc Nephrol 26:2741-52|
|Duque, Juan C; Martinez, Laisel; Mesa, Annia et al. (2015) CD4(+) lymphocytes improve venous blood flow in experimental arteriovenous fistulae. Surgery 158:529-36|
|Ding, Wen; Li, Jihe; Singh, Jayanti et al. (2015) miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice. Cardiovasc Res 106:131-42|
|Martinez, Laisel; Gomez, Camilo; Vazquez-Padron, Roberto I (2015) Age-related changes in monocytes exacerbate neointimal hyperplasia after vascular injury. Oncotarget 6:17054-64|
|Jagarapu, Jawahar; Kelchtermans, Jelte; Rong, Min et al. (2015) Efficacy of Leukadherin-1 in the Prevention of Hyperoxia-Induced Lung Injury in Neonatal Rats. Am J Respir Cell Mol Biol 53:793-801|
|Gomez, Camilo; Martinez, Laisel; Mesa, Annia et al. (2015) Oxidative stress induces early-onset apoptosis of vascular smooth muscle cells and neointima formation in response to injury. Biosci Rep 35:|
|Greka, Anna; Weins, Astrid; Mundel, Peter (2014) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 370:1263-6|
Showing the most recent 10 out of 16 publications