Effects on Biomarkers for Cardiovascular Disease

According to the World Health Organization, cardiovascular diseases remain the number one cause of death globally. By 2030, over 23 million will die from cardiovascular diseases which represent a group of disorders of the heart and blood vessels http://www.who.int/cardiovascular_diseases/en/. Heart attacks and strokes are mainly caused by a blockage that prevents blood from flowing to the heart muscle or from supplying the brain. The most common cause is a build-up of fatty deposits on the inner walls of the blood vessels that supply the heart or brain. The blood vessels become narrower and less flexible, also known as atherosclerosis (or hardening of the arteries). The blood vessels are then more likely to become blocked by blood clots. When this happens, the blocked vessels cannot supply blood to the heart and brain, which then become damaged.

Cardiovascular Disease and mushrooms

Elevated levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels, reduced high-density lipoprotein cholesterol (HDL-C) levels, high blood pressure (hypertension), diabetes, overweight, obesity, lack of physical activity and smoking are all risk factors for cardiovascular disease. More recently, cardiovascular disease is described as an inflammatory condition – as early events in atherosclerosis involve release of pro-inflammatory stimuli which then can increase molecules that allow a “sticky arm” to be extended into the blood of the inner aorta. Here they can attract and bind, or catch, immune cells such as monocytes encouraging movement into the aortic wall where damage begins by fatty plaque, or atheroma, formation.

Mushrooms are a low calorie/kilojoule food; have virtually no fat, saturated fat and trans fatty acids; are low in sodium; and contain no dietary cholesterol. Mushrooms provide potassium, an important electrolyte in the body that lessens the effect of salt on blood pressure. Mushrooms also contain dietary fiber - soluble fiber has been linked to lowering serum cholesterol.

Studies suggest that fruit and vegetable consumption lowers cardiovascular risk in part due to antioxidant activity and immunomodulation since oxidative stress and inflammation are features of early events leading to heart disease. Mushrooms contain bioactive compounds including L-ergothioneine and polyphenols which have antioxidant properties (see section on antioxidants). Both common and specialty mushroom inhibit adhesion molecule expression and in vitro binding of monocytes to human aortic endothelial cells in a pro-inflammatory environment. Lowering adhesion molecules expression interrupts early processes in the development of plaque build-up (http://www.nutritionj.com/content/9/1/29) .

From the Executive Summary

 

Cardiovascular Risk: Plasma cholesterol in animal models has been shown to be reduced by mushroom consumption. The hypocholesterolemic effect appears to be due partly to an increased rate of low density lipoprotein and high-density lipoprotein catabolism. While some studies have postulated eritadenine or angiotensin I – converting enzyme inhibitory peptides as the hypocholesterolemic agents, similar effects on cholesterol, and other biomarkers of cardiovascular risk have been demonstrated by consumption of mushroom fibre. Such a cholesterol-lowering effect has also been reported in humans.

Studies in humans

 

The effect of Oyster mushrooms on reduction of blood glucose, cholesterol and triglycerides in diabetic patients has been evaluated in a clinical investigation of 89 subjects. Mushroom consumption significantly reduced systolic and diastolic blood pressure, lowered plasma glucose, total cholesterol and triglycerides significantly, whereas there was no significant change in body weight. There were no deleterious effects on liver or kidney function (Khatun et al., 2007).

The effects of protein-bound polysaccharides (A-PBP and L-PBP), extracted from the mycelia of Agaricus blazei and Lentinus edodes, on serum cholesterol and body weight have been investigated in 90 female volunteers. The data demonstrated a weight-controlling and hypolipidemic effect of both A-PBP and L-PBP via a mechanism involving absorption of cholesterol (Kweon et al., 2002).

Animal model (mice) studies

A study has been conducted to investigate the hypocholesterolemic effect of a hot-water fraction (HW) from cultured mycelia of Cordyceps sinensis. In mice fed a cholesterol-free diet and those fed a cholesterol-enriched diet, body and liver weights were not significantly different from those of the controls. The serum total cholesterol (TC) of all mice groups administered HW (150 and 300mg/kg/d, respectively) with the cholesterol-enriched diet decreased more than in the control group. Among the mice fed the cholesterol-enriched diet, HW also increased the high-density lipoprotein (HDL) cholesterol level, but decreased the very low-density lipoprotein plus low-density lipoprotein (VLDL+LDL) cholesterol level. The changes in HDL-and VLDL+LDL­cholesterol levels consequently decreased the atherogenic value. The results indicated that HW in rats administered a cholesterol-enriched diet decreased the plasma cholesterol level. The 300mg/kg dose had a significant effect on the serum total cholesterol level (Koh et al., 2003).

A hot water extract from Ganoderma lucidum has been shown to have an antioxidative effect against heart toxicity in mice. Ganoderma lucidum exhibited a dose-dependent antioxidative effect on lipid peroxidation and superoxide scavenging activity in mouse heart homogenate. Furthermore, this result indicated that heart damage induced by ethanol showed a higher malonic dialdehyde level compared with heart homogenate treated with Ganoderma lucidum. The authors concluded that this effect of Ganoderma lucidum may protect the heart from superoxide induced damage (Wong et al., 2004).

Anti-atherosclerotic effects of Pleurotus eryngii (Eringi), Grifola frondosa (Maitake), and Hypsizygus marmoreus (Bunashimeji), have been demonstrated in atherosclerosis-susceptible C57BL/6J, apolipoprotein E-deficient (apoE(-/-)) mice. Atherosclerotic lesions were significantly decreased in the 3 mushroom groups compared to the control group. The anti-atherosclerotic effect was partially via lowering of serum total cholesterol concentrations (Mori et al., 2008). Agaricus sylvaticus has also been reported to prevent the onset of atheroma plaques in hypercholesterolemic rabbits (Percario et al., 2008).

Auricularia auricula polysaccharides have also recently been reported to have a positive effect on heart function of aged mice, possibly via their significant antioxidant activity (Wu et al., 2010).

Animal model (rat and larger animal) studies

Blood pressure of spontaneously hypertensive rats (SHR) has been shown to be significantly reduced by Maitake feeding for 8 weeks, beginning at a time when the animals were 10 weeks of age with well-established high blood pressure. There was no difference in the plasma total and free cholesterol, triglyceride and phospholipid levels between the Maitake fed animals and the control. Conversely, Shiitake mushroom intake did not reduce blood pressure, but significantly lowered free plasma cholesterol, triglyceride and phospholipid in comparison to the control (Kabir and Kimura, 1989).

A hypocholesterolemic effect has been shown with Oyster mushrooms (Pleurotus ostreatus) in rats with Streptozotocine-induced diabetes. Oyster mushroom (4% dry oyster mushroom fruit body) lowered cholesterol content by more than 60% in the liver although it did not significantly affect either the serum triacylglycerol level or the content in liver (Bobek et al., 1991). Similar results have been observed in rats with a hereditary hypersensitivity to dietary cholesterol (Bobek et al., 1990). The hypocholesterolemic effects of Oyster mushrooms has been demonstrated to be dose-dependent (Bobek et al., 1997). A similar hypocholesterolemic effect of the oyster mushroom (Pleurotus ostreatus) was also observed in hamsters (Bobek et al., 1993b) and in rabbits (Bobek and Galbavy, 1999).

Hypocholesterolemic activity of the agent eritadenine present in Lentinus edodes has been reported (Enman et al., 2007). Hypocholesterolemic activity by Hatakeshimeji (Lyophyllum decastes Sing.) mushroom has been demonstrated in rats (Ukawa et al., 2001b), and by Ganoderma lucidum in hamsters and mini-pigs (Berger et al., 2004). Other mushroom varieties that have been shown to have hypocholesterolemic properties include Volvariella volvacea (straw mushroom) (Cheung, 1998, Cheung, 1996a), Auricularia auricula (Tree-ear) and Tremella fuciformis (White jelly-leaf) (Cheung, 1996b) and Pleurotus ostreatus (Oyster mushroom) (Hossain et al., 2003). In contrast to the above studies, farm-grown Agaricus campestris in the diet of rats did not affect plasma and liver cholesterol concentrations (Beynen et al., 1996).

Plasma cholesterol concentration in rats has been shown to be reduced by feeding of mushroom (Agaricus bisporus) fibre. The results demonstrated that mushroom fiber (and sugar beet fiber) lowered the serum total cholesterol level by enhancement of the hepatic low density lipoprotein (LDL) receptor mRNA (Fukushima et al., 2000). Similar cholesterol-lowering effects in rats of Maitake (Grifola frondosa) fiber, Shiitake (Lentinus edodes) fiber, and Enokitake (Flammulina velutipes) fiber have also been reported (Fukushima et al., 2001).

The effects of Shiitake (Lentinus edodes, LE) and autolyzed- (fermented-) Shiitake (autolyzed-LE) on blood pressure and serum fat levels of spontaneously hypertensive rats (SHR) have been studied. The animals of the autolyzed-LE group showed significantly lower blood pressure compared to the control or LE group. The serum levels of total cholesterol (TC), triglyceride and phospholipid of the groups fed with LE and autolyzed-LE were lower than those of the control group, and atherogenic index [(TC-HDL­C)/HDL-C] improved significantly in 21 days. It was suggested that the serum TC decline is the action of eritadenine that is contained in the Shiitake mushroom. An inhibitory activity of the angiotensin I-converting enzyme (ACE) was compared between of LE and autolyzed-LE. Autolyzed-LE showed higher inhibitory activity than LE against the ACE. The results suggested that the hypotensive action of autolyzed-LE was due to concomitant ACE inhibitory activities of peptides and gamma-aminobutyric acid contained in higher amounts during the autolysis of LE (Watanabe et al., 2002).

The effects of four edible mushrooms (Shiitake, Hiratake, Eringi, Hatakeshimeji) on serum and hepatic lipid levels have been investigated in rats. The results showed that the body weight and food intake of the four mushroom groups were significantly lower than those of the control group. The liver level of triacylglycerols was significantly lower in the Hiratake, Eringi and Hatakeshimeji groups than that in the control group. The serum cholesterol levels of the mushroom groups were also significantly lower than that of the control group showing that these four edible mushrooms suppress hepatic triacylglycerol accumulation, and lower blood lipid levels (Ohtsuki et al., 2006). The Bunashimeji mushroom (Hypsizigus marmoreus) has also been shown to suppress hepatic triacylglycerols accumulation and lowers blood cholesterol levels in mice (Ohtsuki et al., 2007). Exo-biopolymers (EXBP) produced from a submerged mycelial culture of Ganoderma lucidum has also bben shown to lower liver total cholesterol, triglyceride, and phospholipid levels by 22.4, 23.1, and 12.9%, respectively. Furthermore, the high-density lipoprotein (HDL) cholesterol and ratio of HDL cholesterol to total cholesterol were significantly increased (Yang et al., 2002b).

Maitake mushroom consumption has also been shown, in Sprague-Dawley rats, to have the ability to alter lipid metabolism by inhibiting both the accumulation of liver lipids and the elevation of serum lipids. Further studies are needed to determine the mechanism of activity of Maitake mushrooms and to establish whether their action in humans is similar to that observed in the rat model (Kubo and Nanba, 1996). A further study by the same group, using the same rat model system, has also shown that consumption of dried Maitake powder (mixed with a basic high-cholesterol rat chow) cholesterol, triglyceride and phospholipids in the serum of rats in the Maitake-feed group were suppressed by 0.3­-0.8 times those in animals fed the basic feed.

Weights of liver and epididymal fat-pads were significantly lower (0.6-0.7 times) than those in the basic feed group, indicating that Maitake inhibited lipid accumulation in the body. Liver lipids were also measured and the values were found to be decreased by Maitake administration. Measurement of the amount of total cholesterol and bile acid in faeces showed the ratio of cholesterol-excretion had increased 1.8 fold and bile acid-excretion 3 fold by Maitake treatment suggesting that Maitake consumption may help to improve the lipid metabolism as it inhibits both liver lipid and serum lipids which were increased by the ingestion of high-fat feed (Kubo and Nanba, 1997).

The straw mushroom Volvariella volvacea has been reported to produce a hypotensive response in animals. An aqueous extract of the mushroom (SME) was prepared and given through intravenous injections to normotensive rats. The blood pressure changes produced by SME alone or in the presence of various drugs were studied. An i.v. injection of SME produced a hypotensive effect in rats with an ED50 of 25mg dry weight/kg body weight. SME did not increase urinary excretion or sodium diuresis. It produced positive chronotropic and inotropic effects on isolated right atria and induced contraction of isolated tail artery strips. This latter contractile response was inhibited by antagonists of serotonin and alpha-adrenoceptor, ketanserin and phentolamine respectively. Partial purification using dialysis and liquid chromatography revealed that the hypotensive active substances had molecular weights between 8,000 -12,000 daltons and were heat stable and resistant to trypsin digestion (Chiu et al., 1995).

In vitro studies

Angiotensin-converting enzyme (ACE) inhibitory activity (which has an effect on blood pressure reduction) has been demonstrated in the culture broth from Flammulina velutipes (strain 414). Nutritional requirements for the production of ACE inhibitory activity from F. velutipes were shown to include sucrose, ammonium acetate, and glutamic acid (Kim et al.  2002). Production and characterization of an anti-hypertensive angiotensin I-converting enzyme inhibitor has also been reported from Pholiota adiposa (Koo et al., 2006) and Hatakeshimeji (Lyophyllum decastes Sing.) (Ukawa et al., 2001a).