Cardiovascular disease (CVD) is the leading cause of death worldwide (123), and anything that can delay or help prevent CVD will make a significant impact in both economic- and health-related terms. Established risk factors for CVD include hypertension, hypercholesterolaemia, diabetes mellitus, smoking, and increased thrombotic index, and there is an ever-increasing list of new CVD risk factors and predictors, such as homocysteine, C-reactive protein, and oxidative stress. Modulating risk factors is the key to primary prevention of CVD (141).
Morigiwa et al. (79) reported that isolated triterpenes from the fruit body of G. lucidum inhibited angiotensin-converting enzyme (ACE), suggesting a potential role for G. lucidum in the modulation of blood pressure. Three days of oral administration of mycelium extract to hypertensive rats had no hypotensive effect, but the authors reported that administration of the mycelium culture media (water and bran base) produced a decrease in blood pressure lasting up to 25 hr (142), implying production and release of hyptensive agents from the mycelium. However, this study was poorly designed and described, and apparently uncontrolled. In a study with nor-motensive animals (143), an ethanol-precipitable fraction of a water extract of mycelium and medium was given by intravenous injection. Blood pressure reportedly decreased in anesethetized, but not in conscious, rabbits, but did decrease in conscious rats. Heart rates did not change, but the authors reported a decreased activity in exposed renal nerves. However, this study was also uncontrolled, and results are difficult to interpret.
In a 6-month human supplementation study in Japan (144), 53 patients (40 hypertensive and 13 normotensive or mildly hypertensive control subjects) took 1.5 g (as capsules) per day of G. lucidum extract. After 10 days significant decreases were reported in the systolic and diastolic pressures of the hypertensive subjects, and these remained decreased until the end of the trial. The authors concluded that oral intake of G. lucidum resulted in lowered blood pressure in essential hypertension. The lack of significant effect in control subjects could imply an indirect effect of G. lucidum on blood pressure; however, it must be noted that there was no placebo-controlled group in this study. It is of interest that 6 months of supplementation with G. lucidum was not associated with any evidence of renal or hepatic toxicity, as no deleterious changes were seen in plasma biomarkers of kidney or liver function. Furthermore, there was a small (around 7%) but significant decrease in total cholesterol concentration (144). A cholesterol-lowering effect was also seen in a study using an in vitro rat liver homogenate model (145). One triterpene (the oxygenated lanosterol, Compound VI) from G. lucidum was reported to show a marked inhibitory effect on cholesterol synthesis from dihydrolanosterol, with 84% inhibition at 40 ||M (145). The hypocholesterolaemic effect may be mediated by effects on cholesterol biosynthesis and by possible triterpene-mediated effects on blockage of cholesterol absorption (7,11,145).
Platelet aggregation and agents that mediate proliferation of vascular smooth muscle play a role in thrombosis and vascular spasm, key players in CVD (146). Several compounds from the G. lucidum mushroom have been reported to have antagonistic effects on platelet aggregation. Adenosine suppresses platelet aggregation, and a dried water extract of G. lucidum was reported to have an adenosine concentration of >40 mg/100 g (147). Administration of the adenosine derivative, 5-deoxy-5-methylsulfinyladeno-sine, isolated from G. lucidum, showed inhibitory effects on induction of platelet aggregation in rabbit plasma, but the effect was not as strong as that of adenosine (148).
Su et al. (149-151) showed that the triterpene ganodermic acid S (GAS), isolated from the mushroom's mycelia, inhibited platelet response to collagen, and GAS showed an additive inhibitory effect on collagen-induced platelet aggregation in the presence of prostaglandin E1. Collagen-induced aggregation is mediated by thromboxane A2(TXA2)-dependent signaling pathways. TXA2 is a potent inducer of platelet activation, and agents, such as GAS, that inhibit the action of TXA2, directly or indirectly, may have important therapeutic applications in lowering CVD risk (152).
G. lucidum has also been reported to have other antithrombotic effects. Choi and Sa (110) reported that a metalloprotease (likely a zinc metal-loprotease) isolated from the mycelium of G. lucidum increased the throm-bin-induced clotting time of human plasma in vitro, by competitive inhibition of the interaction between thrombin and fibrinogen, as well as having a fi-brinolytic effect.
Diabetes mellitus is a risk factor considered equivalent to established coronary heart disease (153). Components of G. lucidum have been shown to have a hypoglycemic effect in animals. Ganoderans A and B, two polysaccharides isolated from fruit body water extracts and administered (dose of 100 mg/kg) by intraperitoneal injection to normal and alloxan-induced diabetic hyperglycaemic mice, significantly decreased (by up to 50%) the plasma glucose concentrations, and the hypoglycemic effect was still evident after 24 hr (61). Using a mouse model, ganoderan B was also reported to increase plasma insulin, decrease hepatic glycogen content, and modulate the activity of glucose-metabolizing enzymes in the liver (154). The same group reported that a third polysaccharide (ganoderan C) isolated from G. lucidum also showed significant hypoglycemic effects in mice, and that ganoderan B increased plasma insulin levels in both normal and glucose-loaded mice (57,154). In a small (n = 8) clinical trial (46) two type 1 and two type 2 diabetes mellitus patients were given 3 g/day of a commercial G. lucidum supplement for 2 months, while two patients in each group were given conventional therapy (insulin or oral hypoglycemic agent). After 2 months of treatment, all patients were reported to exhibit improvement in their blood glucose levels. However, the poor design, the lack of detail, and the small number of subjects mean that this study and its results have little in the way of scientific credibility, and further study is needed on potential hypoglycemic effects of G. lucidum in humans.
CVD can be regarded as an inflammatory disorder. Inflammation-induced increases in acute-phase proteins, such as fibrinogen, are associated with increased CVD risk, and even small increases in highly sensitive C-reactive protein (hsCRP) are regarded as predictive of CVD (155). Anti-inflammatory agents, therefore, may be useful in lowering CVD risk. G. lucidum has been reported to have anti-inflammatory activity, and this is described in more detail in the next section. CVD is also regarded as having a strong association with oxidative stress (155). This is relevant in that G. lucidum has also been reported to have antioxidant properties. These will be described later.
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