Oral Intake of Hydrogen-rich Water Inhibits Intimal Hyperplasia in Arterialized Vein Grafts in Rats

Abstract

Introduction: Arterialized vein grafts often fail due to intimal hyperplasia (IH), which remains a serious concern for patients after arterial bypass surgery due to a lack of pharmacological agents that prevent IH. Hydrogen gas potently protects organs and cells from many insults via its anti-inflammatory, antiapoptotic, and antioxidant properties. We investigated the efficacy of oral administration of hydrogen-rich water (HW), a feasible approach for hydrogen intake, for prevention of IH. Methods: The inferior vena cava was excised from donor rats, stored in cold Ringer solution for 2 hours, and placed as an interposition graft in the abdominal aorta of syngeneic Lewis rats. HW for drinking was generated by immersing a magnesium stick in tap water (Mg + 2H2O → Mg (OH)2+ H2). Beginning on the day of graft implantation, recipients were given, as drinking water, either regular tap water (RW), HW, or HW that had been subsequently degassed (DW) (Table1). Smooth muscle cell migration in culture was assessed using A7r5 cells. Results: Six weeks after grafting, the grafts in the rats given RW or DW had developed IH, accompanied by increased expression of 4HNE and 8-OHdG, oxidative injury markers. HW significantly suppressed intimal hyperplasia (Table 1) and expression of 4HNE and 8-OHdG. One week after grafting, the mRNAs for ICAM and endothelin receptor –A were upregulated in the vein grafts of rats that received RW or DW. This upregulation was attenuated in grafts of rats that received HW. Activation of p38 MAPK, matrix metalloproteinase (MMP)-2 andMMP-9 was also significantly inhibited in grafts that received HW as compared with those in rats that received RW or DW. Scanning electron microscopy revealed endothelial denudation with deposition of platelets and microthrombi, 1 week after engrafting, in the vein grafts of rats that received RW or DW. HW attenuated these changes; the grafts exhibited improved endothelial integrity with less platelet and white blood cell aggregation.No adverse effects, such as diarrhea or body weight loss, were seen during the follow-up period. in rat smooth muscle cell (A7r5) cultures, hydrogen treatment for 24 hours reduced smooth muscle cell migration and did not affect cell proliferation. Conclusions: Drinking HW significantly reduced neointima formation after vein grafting in rats. Drinking HW may have therapeutic value as a novel and alternative therapy for IH, which could also easily be incorporated into daily life. the therapeutic effects of HW may be related to hydrogen's anti-inflammatory actions or ability to decrease cell adhesion. Hydrogen merits further investigation for therapeutic use in the patients who undergo vein grafting. Table 1Drinking Water for Each Experimental Group Drinking water Mg stick Mg conc (mg/L ) H2 Conc (mM) pH IH at 6 weeks (n=6) (Intima/intima+media) Regular water (RW) No <1 .0 0 6.8-7.1 49.0±10.4 Degassed water (DW) Yes 6.2-7.9 0 9.2-9.9 52.2 ± 11.1 ∗ p<0.05 vs RW. Hydrogen water (HW) Yes 6.1-7.9 0.55-0.65 9.3-9.8 21.0 ± 13.9 ∗ p<0.05 vs RW. ∗ p<0.05 vs RW. Open table in a new tab