Nattokinase Attenuates Retinal Neovascularization Via Modulation of Nrf2/HO-1 and Glial Activation

Abstract

Purpose Nattokinase (NK), an active ingredient extracted from traditional food Natto, has been studied for prevention and treatment of cardiovascular diseases due to various vasoprotective effects, including fibrinolytic, antihypertensive, anti-atherosclerotic, antiplatelet, and anti-inflammatory activities. Here, we reported an antineovascular effect of NK against experimental retinal neovascularization. Methods The inhibitory effect of NK against retinal neovascularization was evaluated using an oxygen-induced retinopathy murine model. Expressions of Nrf2/HO-1 signaling and glial activation in the NK-treated retinae were measured. We also investigated cell proliferation and migration of human umbilical vein endothelial cells (HUVECs) after NK administration. Results NK treatment significantly attenuated retinal neovascularization in the OIR retinae. Consistently, NK suppressed VEGF-induced cell proliferation and migration in a concentration-dependent manner in cultured vascular endothelial cells. NK ameliorated ischemic retinopathy partially via activating Nrf2/HO-1. In addition, NK orchestrated reactive gliosis and promoted microglial activation toward a reparative phenotype in ischemic retina. Treatment of NK exhibited no cell toxicity or anti-angiogenic effects in the normal retina. Conclusions Our results revealed the anti-angiogenic effect of NK against retinal neovascularization via modulating Nrf2/HO-1, glial activation and neuroinflammation, suggesting a promising alternative treatment strategy for retinal neovascularization.

Recent Advances in Nattokinase-Enriched Fermented Soybean Foods: A Review

“…NK is also an effective treatment for other diseases, due to its protease properties. NK can be an alternative treatment strategy for retinal neovascularization by the antiangiogenic effect [149]. NK can treat patients with proliferative vitreoretinal disease by hydrolyzing collagen fiber [150].…”

Neurosensory Alterations in Retinopathy of Prematurity: A Window to Neurological Impairments Associated to Preterm Birth

“…Although no clinical evidence indicates that gliosis may participate in ROP pathogenesis, results in preclinical models suggest this possibility. In fact, it has been demonstrated that gliosis, and in particular Müller cell activation, is a feature of OIR rodents [ 13 ] and that in these animals, maneuvers attenuating Müller cell gliosis reduce retinal neurovascular degeneration and preserve retinal function [ 153 , 154 , 155 ].…”

Biotechnology, Bioengineering and Applications of <em>Bacillus </em>Nattokinase

“…Compared with traditional thrombolytic drugs, nattokinase has a relatively lower risk of delivery, a larger tolerable dose, and without side effects such as gene mutation and chromosomal aberration induction [5,6]. More importantly, nattokinase also has various pharmacological effects, such as improving microcirculation and lowering blood pressure [7], anticoagulation [8], preventing atherosclerosis [9], relieving retinal angiogenesis [10], anticancer [11], inhibiting inflammation and oxidative stress, etc [12]. In conclusion, nattokinase is a new type of thrombolytic drug with great application potential [13].…”

“…In addition to the research of nattokinase in the field of thrombosis and hypertension treatment, nattokinase can also be used as a drug or adjuvant to treat diseases such as cancer [11], Alzheimer's disease (AD) [97], retinopathy [10], hyperlipidemia [98] and oral mucositis [99]. Nattokinase has broad prospects in the field of cancer treatment and is expected to become an effective means of cancer treatment in the future.…”

“…Diseases such as retinopathy of prematurity, diabetic retinopathy, and retinal vein occlusion all cause irreversible visual impairment and blindness through the formation of pathological neovascularization. Nattokinase attenuated neovascularization in the retina of mice with oxygen retinopathy but activated the Nrf2/HO-1 pathway to ameliorate ischemic retinopathy [10]. In addition, nattokinase has been proved to induce posterior vitreous detachment, and it is a useful drug as a vitreous cleavage enzyme, which has application prospects in the treatment of proliferative vitreoretinal diseases [110].…”