This proposal addresses a problem of great clinical significance: the lack of effective therapies to limit neurovascular injury and promote repair during the early stages of potentially blinding ischemic retinopathies. We propose studies designed to show that increasing activity of the arginase 1 enzyme in immune cells offers a novel and highly effective strategy for limiting neurovascular injury and promoting retinal tissue repair in the early stages of ischemic retinopathy. Our previous studies have shown that the urea hydrolase enzyme arginase is critically involved in neurovascular injury in diabetic retinopathy (DR), ischemia/reperfusion injury (IR) and oxygen-induced retinopathy (OIR). Arginase metabolizes L-arginine to form polyamines, proline, and glutamate. Catabolic products of polyamine oxidation and glutamate can promote oxidative injury and cell death. Excessive arginase activity also can reduce the supply of L-arginine substrate needed for production of nitric oxide (NO) by NO synthase (NOS). Our studies in models of DR have shown that increased expression/activity of the arginase 1 (A1) isoform is involved in vascular dysfunction and premature senescence by a mechanism involving decreased NO formation by endothelial NOS (eNOS). In contrast, our studies in models of IR and OIR indicate that the arginase 2 (A2) isoform is involved in neurovascular injury by mechanisms involving upregulation of inducible NOS (iNOS) and tumor necrosis factor-? (TNF?) which leads to cell death via activation of the TNF receptor interacting protein 3 kinase (RIP3)/dynamin-related protein 1 (DRP1) axis. Preliminary data also show that deletion of A2 limits this damage by a mechanism involving increased A1 expression and suppressed iNOS-mediated NO formation. A1 deletion globally or in myeloid- derived cells, or M? depletion aggravates the injury whereas intravitreal injection of Pegylated recombinant A1 (PegA1) limits damage. Based on our prior work and preliminary data, we hypothesize that A1 protects against retinal ischemic neurovascular injury by reducing iNOS levels and promoting M?/myeloid cell-mediated pro- survival function. This will be tested by the following aims:
Aim 1 will determine the role of A1 expression in IR- induced neurovascular injury.
Aim 2 will determine whether A1 limits IR-induced injury by promoting reparative M?.
Aim 3 will determine the role of A1 in OIR-induced neurovascular injury and test its potential in therapeutic repair. If successful, the proposed studies will represent a paradigm shift in the field of retinopathy research by identifying A1 as a mediator of neuroprotection and vascular repair.
This proposal addresses a problem of great clinical significance: the lack of effective therapies to limit neurovascular injury and promote repair during the early stages of potentially blinding ischemic retinopathies. We propose studies designed to show that increasing activity of the arginase 1 enzyme in immune cells offers a novel and highly effective strategy for limiting neurovascular injury and promoting retinal tissue repair in the early stages of ischemic retinopathy.
| Shosha, Esraa; Xu, Zhimin; Narayanan, S Priya et al. (2018) Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1. Int J Mol Sci 19: |
| Fouda, Abdelrahman Y; Xu, Zhimin; Shosha, Esraa et al. (2018) Arginase 1 promotes retinal neurovascular protection from ischemia through suppression of macrophage inflammatory responses. Cell Death Dis 9:1001 |
| Chandra, Surabhi; Fulton, David J R; Caldwell, Ruth B et al. (2018) Hyperglycemia-impaired aortic vasorelaxation mediated through arginase elevation: Role of stress kinase pathways. Eur J Pharmacol 844:26-37 |
| Zhang, Hanfang; Hudson, Farlyn Z; Xu, Zhimin et al. (2018) Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization. Invest Ophthalmol Vis Sci 59:2520-2528 |
| Caldwell, R William; Rodriguez, Paulo C; Toque, Haroldo A et al. (2018) Arginase: A Multifaceted Enzyme Important in Health and Disease. Physiol Rev 98:641-665 |
| Rojas, Modesto A; Shen, Zu T; Caldwell, Ruth B et al. (2018) Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy. Biochim Biophys Acta Mol Basis Dis 1864:2761-2768 |
| Rojas, Modesto; Lemtalsi, Tahira; Toque, Haroldo A et al. (2017) NOX2-Induced Activation of Arginase and Diabetes-Induced Retinal Endothelial Cell Senescence. Antioxidants (Basel) 6: |
| Toque, Haroldo A; Fernandez-Flores, Aracely; Mohamed, Riyaz et al. (2017) Netrin-1 is a novel regulator of vascular endothelial function in diabetes. PLoS One 12:e0186734 |
| Bhatta, Anil; Yao, Lin; Xu, Zhimin et al. (2017) Obesity-induced vascular dysfunction and arterial stiffening requires endothelial cell arginase 1. Cardiovasc Res 113:1664-1676 |
| Yao, Lin; Bhatta, Anil; Xu, Zhimin et al. (2017) Obesity-induced vascular inflammation involves elevated arginase activity. Am J Physiol Regul Integr Comp Physiol 313:R560-R571 |
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