Modulation of circulating macrophage migration inhibitory factor in the elderly.

Aging increases the risk for cardiovascular morbidity and mortality. Chronic low-grade inflammation deteriorates vascular function, increases age-related vascular stiffness, and affects hemodynamics. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) is a major mediator of atherosclerosis. Plasma MIF levels are associated with arterial stiffness, a hallmark of vascular aging. Preclinical studies show that blockade of MIF leads to atherosclerotic plaque regression. Nutritional approaches provide opportunities to counteract age-related inflammation. Following a chronic dietary supplementation with the micronutrient nitrate has been demonstrated to improve vascular stiffness. Whether dietary nitrate affects circulating MIF levels is not known. In a randomized placebo-controlled, double-blinded study, elderly subjects received a dietary nitrate supplementation for 4 weeks. Dietary nitrate led to a decrease in plasma MIF levels in the elderly and to an improvement in vascular functions. This was associated with a reduction in central systolic blood pressure. Our data show that supplementation with dietary nitrate is associated with a reduction of circulating MIF levels along with an improvement in vascular function. This supports the concept of dietary approaches to modulate age-related changes of vascular functions.

Dietary nitrate supplementation improves revascularization in chronic ischemia.

BACKGROUND: Revascularization is an adaptive repair mechanism that restores blood flow to undersupplied ischemic tissue. Nitric oxide plays an important role in this process. Whether dietary nitrate, serially reduced to nitrite by commensal bacteria in the oral cavity and subsequently to nitric oxide and other nitrogen oxides, enhances ischemia-induced remodeling of the vascular network is not known. METHODS AND RESULTS: Mice were treated with either nitrate (1 g/L sodium nitrate in drinking water) or sodium chloride (control) for 14 days. At day 7, unilateral hind-limb surgery with excision of the left femoral artery was conducted. Blood flow was determined by laser Doppler. Capillary density, myoblast apoptosis, mobilization of CD34(+)/Flk-1(+), migration of bone marrow-derived CD31(+)/CD45(-), plasma S-nitrosothiols, nitrite, and skeletal tissue cGMP levels were assessed. Enhanced green fluorescence protein transgenic mice were used for bone marrow transplantation. Dietary nitrate increased plasma S-nitrosothiols and nitrite, enhanced revascularization, increased mobilization of CD34(+)/Flk-1(+) and migration of bone marrow-derived CD31(+)/CD45(-) cells to the site of ischemia, and attenuated apoptosis of potentially regenerative myoblasts in chronically ischemic tissue. The regenerative effects of nitrate treatment were abolished by eradication of the nitrate-reducing bacteria in the oral cavity through the use of an antiseptic mouthwash. CONCLUSIONS: Long-term dietary nitrate supplementation may represent a novel nutrition-based strategy to enhance ischemia-induced revascularization.