Cardiovascular diseases (CVDs) are the most prevalent cause of deaths worldwide. In 2015, the number of CVD-related deaths represented 31% of all deaths globally. To date, there are limited approaches available for the control and/or management of CVD-related mortality. Natto, a cheese-like food made of soybeans fermented with Bacillus subtilis, has been consumed as a traditional food in Asian countries for more than 2000?years. Natto consumption is believed to be a significant contributor to the longevity of the Japanese population. Recent studies demonstrated that a high natto intake was associated with decreased risk of total CVD mortality and, in particular, a decreased risk of mortality from ischaemic heart diseases.[1]

Potent fibrinolytic/antithrombotic effects of Nattokinase

Although natto has been consumed in Asia for thousands of years, the fibrinolytic property of Nattokinase was only discovered in 1987. Since this initial discovery, multiple laboratory and human studies have consistently reported the potent antithrombolytic action of Nattokinase. A considerable amount of work has been performed to evaluate the thrombolytic effects of Nattokinase in vitro and in animal models. Using a rat model, Fujita et al examined the effect of Nattokinase on chemically induced thrombi in the common carotid artery (CCA) and found Nattokinase to be 4 times more potent than plasmin in thrombus dissolution. At a concentration of 2836?FU, Nattokinase lysed 88% of thrombi within 6?hours, and Nattokinase exhibited significant prophylactic antithrombotic effects in vivo. The efficacy of Nattokinase against thrombosis was confirmed in a carrageenan-induced tail thrombosis model. The survival rate of mice with pulmonary thrombosis was increased by Nattokinase and the formation of thrombosis in mice was remarkably inhibited by Nattokinase, demonstrating significant antithrombotic effects. In addition, in a model of rat experimental pulmonary thrombosis, oral administration of Nattokinase led to a decrease in thrombus count and plasma euglobulin lysis time (ELT), as well as an increase in tissue plasminogen activator (tPA), indicating that Nattokinase is capable of activating plasma fibrinolysis in vivo. Omura et al further found that a purified protein layer, NattokinaseCP, which mainly consisted of Nattokinase, had both fibrinolytic and antithrombotic effects, which they described as being similar to that of heparin. In rats, Natto treatment shortened ELT and significantly prolonged partial thromboplastin time compared with a nontreated rat group.[2]

It is now known that Nattokinase not only degrades fibrin directly and effectively but also increases the release of tPA with a subsequent increase in the formation of plasmin. Plasminogen activator inhibitor 1 (PAI-1) is the primary inhibitor of tPA and regulates fibrinolytic activity in the fibrinolytic cascade. In a study investigating the mechanism by which Nattokinase exerted its fibrinolytic effect, Nattokinase enhanced fibrinolysis through cleavage and inactivation of PAI-1. In this study, Nattokinase was shown to cleave active recombinant prokaryotic PAI-1 into low-molecular-weight fragments as well as enhance tissue-type plasminogen activator–induced fibrin clot lysis. The enhanced fibrinolytic activity observed in the absence of PAI-1 appeared to be induced through direct fibrin dissolution by Nattokinase. Nattokinase also enhanced the production of clot-dissolving agents such as urokinase through the conversion of prourokinase to urokinase. Furthermore, Nattokinase was shown to be capable of blocking thromboxane formation resulting in an inhibition of platelet aggregation without producing the side effect of bleeding. Thus, Nattokinase was found to be a potent antithrombotic agent, and, by reducing thrombus formation, was able to slow the progression of plaque formation and reverse evolving atherosclerotic lesions.

Antiplatelet/anticoagulant effects of Nattokinase

Low-dose aspirin (85-100?mg daily), as a potent anticoagulant agent, is widely used for the prevention of heart attacks, stroke, and atherothrombotic diseases. Aspirin exerts its antiplatelet action by inhibiting cyclooxygenase (COX) and subsequently reducing the synthesis of thrombogenic thromboxane A2 (TXA2) in platelets. However, the long-term use of aspirin comes with serious gastrointestinal (GI) side effects and bleeding. In a study comparing the antiplatelet effects of Nattokinase and aspirin, Nattokinase was shown to display excellent antiplatelet aggregation and antithrombotic activities in vitro and in vivo, inhibiting thromboxane B2 formation from collagen-activated platelets. Wang et al found that Nattokinase decreased fibrinogen levels in a cerebral ischaemic model and concluded that this was mediated by a pathway similar to that of aspirin. Natto showed an excellent inhibitory effect on platelet aggregation induced by adenosine 5? diphosphate and collagen. In addition, Nattokinase was found to have positive in vitro haemorheological effects by decreasing red blood cell aggregation and low-shear viscosity. All the above data suggest that Nattokinase could be a good candidate, without any obvious adverse effects, for the improvement of blood flow and possibly superior to aspirin.

Neuroprotective effects of Nattokinase

Nattokinase is capable of degrading amyloid fibrils at neutral pH and normal body temperature, suggesting a role in the treatment of amyloid-related diseases such as Alzheimer disease (AD). The ability of Nattokinase to dissociate amyloid suggested that Nattokinase was a potential drug candidate for amyloid-related disorders and this was confirmed in a recent study involving both in vivo and in vitro models. Oral administration of Nattokinase in the rat model of AD demonstrated a positive effect in modulation of specific factors in the AD pathway. In a rat model of cognitive deficits of AD induced by intoxification of colchicine, nano-nutraceuticals containing Nattokinase were demonstrated to enhance the impaired learning and memory capability and to be effective inhibitors in the suppression of amyloid-β and BACE-1 activity, thus suggesting a neuroprotective efficacy of Nattokinase. Ahmed et al demonstrated that Nattokinase, at a dose of 360?FU/kg, significantly decreased cholinesterase activity, TGF-β, IL-6, and p53 levels accompanied by a significant increase in Bcl-2 levels as compared with an untreated AD control group. Their data suggested that the neuroprotective effect of Nattokinase was due to its proteolytic, anti-inflammatory, and antiapoptotic effects.[3]

In one of the early clinical studies describing the role of Nattokinase in the prevention of stroke progression in patients with acute ischaemic stroke, the authors demonstrated a clear neuroprotective effect in patients. The neuroprotective effects of Nattokinase were demonstrated in a photothrombotic stroke mouse model. Ahn et al suggested that the neuroprotective effect in the ischaemic brain was induced through improved blood flow by inhibiting platelet aggregation and thrombus formation by Nattokinase, as reported in a conference abstract. Oral intake of Nattokinase was also shown to confer neuroprotective effects against focal cerebral ischaemia as evidenced by reduced infarct volume in gerbils through enhanced fibrinolytic activity. Regarding the mechanism by which Nattokinase protects the brain in ischaemic stroke, a study by Ji et al showed that the neuroprotective effect of Nattokinase was associated with its antiplatelet activity, antiapoptotic effect, its ability to relax vascular smooth muscle, and its protection of endothelial cells through increased fibrinolytic activity and facilitating spontaneous thrombolysis.

In summary, compared with traditional antithrombotic and antihypertensive drugs, Nattokinase is characterised by high safety, low cost, simple production process, oral availability, and long in vivo half-life. As such, it is expected to become a new-generation drug for thrombotic disorders or CVDs. Although human trials and clinical studies demonstrate the clinical benefits of Nattokinase in the clinical settings, there remain a number of limitations. However, all the available data are encouraging and promising and further clinical trials are needed to fully examine the prospect of Nattokinase as an alternative medication to tPA, aspirin, warfarin, or newer anticoagulants in the management of CVD. In the near future, it is possible that patients with CVD may need only a single Nattokinase pill to replace multiple drugs administered for the prevention and management of CVD, including tPA, antihypertensives, statins, aspirin, and warfarin.

References

[1]  Sumi H, Hamada H, Tsushima H, Mihara H, Muraki H. A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto; a typical and popular soybean food in the Japanese diet. Experientia. 1987;43:1110–1111.

[2] Weng, Y., Yao, J., Sparks, S., & Wang, K. Y. (2017, February 28). Nattokinase: An Oral Antithrombotic Agent for the Prevention of Cardiovascular Disease. International Journal of Molecular Sciences, 18(3), 523.

[3]  Sumi H, Hamada H, Nakanishi K, Hiratani H. Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinases. Acta Haematol. 1990;84:139–143.