In the DOCA-salt rat model of hypertension, we have shown that treatment with Avemar improved cardiac function, decreased macrophage infiltration resulting in decreased collagen deposition in the ventricular myocardium, reversed an increased stiffness of the left ventricle in the diseased hearts and attenuated oxidative stress measured as plasma malondialdehyde concentrations without changing systolic blood pressure. Our previous studies have shown similar results with inhibitors of the renin-angiotensin system (captopril, candesartan and spironolactone) [27
]. In contrast, we showed that treatment of DOCA-salt rats with L-arginine also decreased blood pressure in the DOCA-salt hypertensive rat [19
]. In the current study, we have further shown that Avemar reversed glucose intolerance, normalized blood pressure and decreased visceral fat deposition in rats fed a high-fat/high-carbohydrate diet.
Since the mechanisms for these cardiovascular actions may be an extension of the anti-oxidant, anti-inflammatory and immunomodulatory mechanisms proposed for the anti-cancer actions of Avemar, it is worthwhile considering whether these actions improve cardiovascular function in disease models (). Avemar produced non-specific inhibition of both cyclooxygenase isoforms, with IC50
values on COX-1 and COX-2 of 100μ
g/ml and 300μ
g/ml, respectively [30
]. In animal studies, COX inhibition decreased myocardial infarct size [24
], produced scar thinning [31
], attenuated cardiopulmonary dysfunction during endotoxemia [31
] and prevented angiotensin II-induced production of superoxide in cardiovascular tissue, together with the decrease in systolic blood pressure and cardiac hypertrophy in vivo
]. Arachidonic acid metabolites are important mediators of inflammation in cardiovascular remodeling; arachidonic acid is released from membranes by phospholipase A2. Inhibition of phospholipase A2 with KH064 prevented an increase in infiltration of inflammatory cells, myocardial collagen deposition and ventricular stiffness in young spontaneously hypertensive rats [29
]. Thus, the decreased collagen deposition following Avemar treatment could be mediated by these known actions as inhibitors of the production of arachidonic acid metabolites. Further, Avemar decreased inflammation through other immunomodulatory mechanisms, such as decreased production of pro-inflammatory cytokines IL-6 and IL-10 in mice with systemic lupus erythematosus [20
] and decreased macrophage infiltration in animal models of rheumatoid arthritis [20
]. Thus, the proposed mechanisms for the anti-cancer effects of Avemar may contribute to the cardiovascular responses in this study.
Potential mechanisms for the beneficial effects of Avemar in diet-induced obese rats.
Furthermore, Avemar contains compounds such as benzoquinones and other plant flavonoids, important agents in controlling oxidative stress and cell damage [19
]. There is extensive literature on the therapeutic use of antioxidant compounds to improve cardiovascular function [20
]. Epidemiological comparisons between populations and studies within populations also support the contention that high plasma concentrations or increased dietary intake of natural antioxidant vitamins may protect against the development of cardiovascular diseases in humans [20
]. Thus, an improvement in oxidative status following Avemar treatment may improve cardiovascular function.
Since inflammatory mediators are important in fat deposition [35
], the anti-inflammatory mechanisms underlying the anticancer effects of Avemar may also decrease abdominal fat deposition. Furthermore, peroxisome proliferator-activated receptor δ
) is of central importance in fat oxidation [35
]. Flavonoids and phenolic acids decreased intracellular triglyceride and glucose phosphate dehydrogenase activity through down-regulating expression of adipogenic transcription factors such a PPARδ
and up-regulating adiponectin expression [38
]. The decrease in fat deposition and weight gain in the rats fed with a high-carbohydrate/high-fat diet with Avemar treatment could be explained by the actions of flavonoids possibly modulating adipogenic transcription factors.
Similarly, the anti-inflammatory mechanisms useful in treatment of cancer may contribute to the changes in glucose tolerance in the high-carbohydrate/high fat diet rats treated with Avemar [39
]. Antioxidants such as N-acetylcysteine, vitamin C and E have also shown anti-diabetic effects possibly by protecting pancreatic β
-cells from glucose toxicity, stimulating insulin secretion and moderately reducing blood glucose levels [41
]. One of the consequences of elevated blood glucose concentrations is the non-enzymatic glycation of proteins such as hemoglobin A1c (HbA1c) and serum albumin [44
]. Plant flavonoids inhibited fructose-mediated glycation of albumin improving the symptoms of diabetes [44
Other components of Avemar such as the benzoquinones may also be cardioprotective. Benzoquinones have very similar characteristics to vitamins and are anti-oxidant compounds. Coenzyme Q10 (ubiquinone) is a naturally occurring benzoquinone, which may prevent cellular damage during myocardial ischemia and reperfusion by its roles in oxidative phosphorylation and membrane stabilization [45
]; diabetes induced a decrease in coenzyme Q plasma levels [46
]. Coenzyme Q10 and alpha-tocopherol treatment decreased glycated HbA1c and pancreatic lipid peroxidation in diabetic rats [40
]. Coenzyme Q10 has also been used in oral form to treat various cardiovascular disorders including angina pectoris, hypertension and congestive heart failure [45
In conclusion, our results show that the fermented wheat germ extract Avemar has a potential role to attenuate the cardiovascular symptoms induced by hypertension, diabetes or the metabolic syndrome while moderating metabolic abnormalities such as glucose tolerance and obesity. Since Avemar is already available in humans as a complementary therapy for cancer, this product could be further evaluated in a clinical setting as an adjunct therapy for preventing cardiovascular and metabolic symptoms.