Dietary Nitrate Supplementation Improves Revascularization in Chronic Ischemia

Hendgen-Cotta UB, Luedike P, Totzeck M, et al (Univ Hosp Düsseldorf, Germany; et al) Circulation 126:1983-1992, 2012^§

Abstract

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 (Figs 1, 4–6).

Figure 1 Effect of dietary nitrate supplementation on perfusion recovery. A, Experimental protocol. B, Original laser Doppler perfusion images (LDPIs) display hind-limb perfusion before and 7 days after excision of the femoral artery. Mice receiving nitrate (middle row) show increased perfusion compared with control animals (left row). Mice receiving antiseptic mouthwash (MW) did not exhibit the nitrate-induced gain of perfusion (right row). C, Nitrate-supplemented mice showed increased perfusion recovery in chronic hind-limb ischemia (black bars; P < 0.02); this effect was not observed in mice receiving antiseptic mouthwash (gray bars; P < 0.02). Data are expressed as mean±SEM (n = 21–23). (Reprinted from Hendgen-Cotta UB, Luedike P, Totzeck M, et al. Dietary nitrate supplementation improves revascularization in chronic ischemia. Circulation. 2012;126:1983-1992, © 2012, American Heart Association, Inc.)

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