Peripheral artery disease (PAD) may lead to a poor quality of life. Although percutaneous transluminal angioplasty (PTA) is widely used for the treatment of PAD, restenosis remains a major drawback. Hydrogen sulfide (H2S) plays potential roles in many physiological processes, such as vasodilatation and inhibition of smooth muscle cell proliferation. However, little is known regarding its role in arterial restenosis. In this study, we induced atherosclerotic-like lesions in rabbits, and we treated the rabbits with balloon angioplasty (BA) in a similar manner as PTA performed in the clinic. The rabbits were treated with sodium hydrosulfide (NaHS, a donor of H2S) or DL-propargylglycine (PPG, an inhibitor of H2S synthase). Treatment with NaHS significantly inhibited arterial restenosis following BA by reducing the intimal area and the intima/media ratio, while PPG treatment had a tendency to result in more severe restenosis. NaHS treatment significantly reduced smooth muscle cell (SMC) proliferation and elevated SMC apoptosis in the neointima. In contrast, PPG induced a significant increase in SMC proliferation. In conclusion, H2S attenuates the progression of neointimal hyperplasia and inhibits restenosis after BA. This discovery may lead to potential novel therapies, which can improve the prognosis of PAD patients.

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