Yamamoto, M.; Ash, D.; Sudhahar, V.; Zaidi, S. A. H.; Rojas, M. A.; Xu, Z.; Kelley, S.; Caldwell, R. B.; Fukai, T.; Ushio-Fukai, M.

Background: Retinal ischemia contributes to vision loss in ischemic and diabetic retinopathies through oxidative stress, neurovascular injury, and inflammation. Copper (Cu), while essential, can be toxic in excess and is regulated by Cu transporters such as CTR1. However, the role of CTR1 in ischemic retinopathy remains unclear. Methods and Results: Retinal ischemia-reperfusion (IR) injury was induced by elevating intraocular pressure to 110 mmHg for 40 minutes in the right eye of Ctr1 heterozygous and wild-type (WT) mice. In WT mice, IR triggered rapid CTR1 upregulation and increased retinal Cu levels (measured by ICP -MS). IR injury caused retinal ganglion cell loss, inner retinal thinning, vascular degeneration, and apoptosis, all of which were significantly attenuated in Ctr1 heterozygous mice. Ctr1 heterozygous mice also exhibited reduced microglial (Iba1) and glial cells (GFAP) activation and preserved visual function, as assessed by electroretinography. Mechanistically, IR-induced superoxide production (DHE staining), upregulation of NADPH oxidase components (NOX2, p47phox), and NFkB activation were markedly suppressed in Ctr1 heterozygous mice. Treatment with the Cu chelator tetrathiomolybdate similarly reduced retinal thinning, neurovascular damage, apoptosis, gliosis, and oxidative stress after IR injury. Conclusions: CTR1 plays a central role in mediating Cu-dependent oxidative stress, neurovascular degeneration, and inflammation following retinal IR injury. Targeting the CTR1-Cu axis may represent a novel therapeutic strategy for ischemic retinopathy.