Molecular mechanisms of hydrogen sulfide against uremic accelerated atherosclerosis through cPKCβII/Akt signal pathway

Abstract

Background Cardiovascular disease is the most common complication and leading cause of death in maintenance hemodialysis patients. The protection mechanism of hydrogen sulfide (H2S) and the specific role of conventional protein kinase C βII (cPKCβII)/Akt signaling pathway in the formation of atherosclerosis is still controversial. Methods 8-week-old male ApoE−/− mice were treated with 5/6 nephrectomy and high-fat diet to make uremia accelerated atherosclerosis (UAAS) model. Mice were divided into normal control group (control group), sham operation group (sham group), UAAS group, L-cysteine group (UAAS+L-cys group), sodium hydrosulfide group (UAAS+NaHS group), and propargylglycine group (UAAS+PPG group). Western blot was used to detect cPKCβII activation, Akt phosphorylation and endothelial nitric oxide synthase (eNOS) expression in mice aorta. Results The membrane translocation of cPKCβII in UAAS group was higher than sham group, and L-cys or NaHS injection could suppress the membrane translocation, but PPG treatment resulted in more membrane translocation of cPKCβII (P < 0.05, n = 6 per group). Akt phosphorylation and the eNOS expression in UAAS group was lower than sham group, and L-cys or NaHS injection could suppress the degradation of Akt phosphorylation and the eNOS expression, but PPG treatment resulted in more decrease in the Akt phosphorylation and the eNOS expression (P < 0.05, n = 6 per group). Conclusion Endogenous cystathionine-γ-lyase (CSE)/H2S system protected against the formation of UAAS via cPKCβII/Akt signal pathway. The imbalance of CSE/H2S system may participate in the formation of UAAS by affecting the expression of downstream molecule eNOS, which may be mediated by cPKCβII/Akt signaling pathway.

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

“…The role of CSE/H 2 S system and TGF-β/Smad pathway in atherogenic process was discussed respectively in other studies. Meanwhile, we confirmed the protective effect of H 2 S regulating cPKCβII/Akt pathway in UAAS patients against atherosclerosis formation and cardiovascular disease progression in our previous study [16]. But whether other signaling pathways may also participate in this process and how the 5/6 nephrectomy and CSE/H 2 S system affect the plaque formation were still unclear in the previous study.…”

“…Furthermore, abnormalities of H 2 S and TGF-β/Smad signaling pathway could lead to UAAS development in chronic hemodialysis patients with diabetic nephropathy [15]. We also found that endogenous CSE/H 2 S system may protect against the formation of UAAS via cPKCβII/Akt signal pathway [16]. But how the 5/6 nephrectomy and CSE/H 2 S system affect the plaque formation and whether other signaling pathways may also participate in this process were still unclear in the previous study.…”

Beneficial Health Effects of Glucosinolates-Derived Isothiocyanates on Cardiovascular and Neurodegenerative Diseases

“…In the study by Testai et al [ 130 ] the H₂S-donor 4-carboxyphenyl isothiocyanate protected against ischemia/reperfusion (I/R)-mediated myocardial tissue injury [ 130 ]. The endogenous cystathionine-γ-lyase (CSE)/H₂S system protected arteries from atherosclerosis through modulating cPKCβII/Akt signal pathway in mouse uremia accelerated atherosclerosis (UAAS) model [ 131 ]. Future studies may uncover whether ITCs modulate this pathway.…”

“…SFN prevents atherosclerosis through modulating various pathways involved in oxidative stress, inflammation, and lipid metabolism and also prevents restenosis of arteries. SFN inhibits key events in atherosclerosis development and progression through MAPK/AP-1/NF-κB [ 146 ] and Nrf2/ARE pathways and possibly the cPKCβII/Akt (Akt-protein kinase B) signal pathway [ 131 ]. SFN improves morphological, histological, and echocardiographic parameters in MI more than mechanical postC, secondary to upregulation of antioxidant response, inhibition of oxidative stress, lipid peroxidation, inflammation, apoptosis and autophagy [ 62 ].…”

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 ].…”