CSE/H(2)S system alleviates uremic accelerated atherosclerosis by regulating TGF-β/Smad3 pathway in 5/6 nephrectomy ApoE(−/−) mice

BACKGROUND: Hydrogen sulfide (H(2)S) has been shown to inhibit the atherosclerosis development and progression. It is produced by cystathionine γ-lyase (CSE) in the cardiovascular system. In our previous study, it has been shown that CSE/H(2)S system plays a significant role in the changes of uremic accelerated atherosclerosis (UAAS), but the mechanism is not known clearly. METHODS: In this study, we explored the antagonism of CSE/H(2)S system in UAAS and identified its possible signaling molecules in ApoE(−/−) mice with 5/6 nephrectomy and fed with atherogenic diet. Mice were divided into sham operation group (sham group), UAAS group, sodium hydrosulfide group (UAAS+NaHS group) and propargylglycine group (UAAS+PPG group). Serum creatinine, urea nitrogen, lipid levels and lesion size of atherosclerotic plaque in the aortic roots were analyzed. Meanwhile, the expression of CSE, TGF-β and phosphorylation of Smad3 were detected. RESULTS: Compared with sham group, the aortic root of ApoE(−/−) mice in the UAAS group developed early atherosclerosis, the levels of total cholesterol, triglyceride, low-density lipoprotein-cholesterol, serum creatinine and urea nitrogen were also higher than that in the sham group. NaHS administration can inhibit the development of atherosclerosis, but PPG administration can accelerate the atherosclerosis development. Meanwhile, the protein expression levels of CSE and TGF-β and phosphorylation of Smad3 significantly decreased in the UAAS mice. Treatment of UAAS mice with NaHS inhibited TGF-β protein expression and Smad3 phosphorylation decrease, but PPG treatment had the opposite effect. CONCLUSIONS: The CSE/H(2)S system is of great importance for treating atherosclerosis in patients with chronic kidney disease, and it may protect the vascular from atherosclerosis through the TGF-β/Smad pathway.