CSE/H2S system alleviates uremic accelerated atherosclerosis by regulating TGF-β/Smad3 pathway in 5/6 nephrectomy ApoE−/− mice

Abstract

Background Hydrogen sulfide (H2S) 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/H2S 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/H2S 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/H2S 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.

Overview on hydrogen sulfide-mediated suppression of vascular calcification and hemoglobin/heme-mediated vascular damage in atherosclerosis

“…Chronic kidney disease markedly accelerates both arterial calcification and atherosclerosis [ 97 , 98 ]. In murine model of uremia accelerated atherosclerosis (UAAS), uremic mice develop early atherosclerosis that is counteracted by NaHS administration [ 99 ]. In UAAS mice, the expression of CSE and transforming growth factor-β (TGF-β) are lowered, Smad3 phosphorylation decreases and all these effects are compensated by NaHS.…”

“…In UAAS mice, the expression of CSE and transforming growth factor-β (TGF-β) are lowered, Smad3 phosphorylation decreases and all these effects are compensated by NaHS. Importantly, the CSE inhibitor propargylglycine accelerates atherosclerosis in UAAS mice [ 99 ] suggesting the protective role of CSE/H 2 S and the downstream TGF-β/Smad3 signaling in UAAS. Others have found that the protective function of H 2 S in UAAS is, at least partly, mediated by the novel protein kinase-δ/Akt pathway [ 100 ] and by the conventional protein kinase C βII/Akt signaling [ 101 ].…”

The Potential of Hydrogen Sulfide Donors in Treating Cardiovascular Diseases

“…Another study reports that treatment with alpha-lipoic acid or NaHS can attenuate diabetes-induced vascular dysfunctions in SMC in rats by elevating H 2 S levels and reducing autophagy by targeting the AMPK/mTOR pathway [ 202 ]. Similarly, NaHS treatment prevents the development of atherosclerosis in uremic-accelerated atherosclerotic ApoE -/- mice through the suppression of TGF-β/Smad3 and activation of the conventional PKC βII/AKT/eNOS pathway [ 203 , 204 ]. A recent study also showed that treatment of diabetes-stimulated atherosclerotic cells and mice with GYY4137 significantly reduces the elevation of pro-inflammatory activities by promoting the activation of PI3K/AKT and the deactivation of NLRP3 and Toll-like receptor-4 signaling [ 205 , 206 ].…”