Abstract
Background: Cardiovascular disease is the most common complication and leading cause of death in maintenance hemodialysis patients. Previous studies have found that disorders of cystathionine-gamma-lyase/hydrogen sulfide (CSE/H2S) system in maintenance hemodialysis patients are correlated with the risk of cardiovascular disease. Although the role of CSE/H2S system in UAAS has been preliminarily explored, the molecular mechanism of CSE/H2S is still not systematically elaborated, and the molecular mechanism of nPKCδ and its related signaling pathway in UAAS is still not thoroughly studied. Methods: Forty chronic kidney disease (CHD) patients were studied and the activation of nPKCδ in peripheral blood mononuclear cells (PBMCs) were detected. ApoE−/− mice aged 6 weeks were treated with 5/6 nephrectomy and high-fat diet to make UAAS model. They were divided into Sham group (Sham group), UAAS group (UAAS group), UAAS+L-cysteine group (UAAS+L-cys group), UAAS+sodium hydrosulfide group (UAAS+NaHS group) and UAAS+propargylglycine group (UAAS+PPG group). The UAAS+L-cys group, UAAS+NaHS group and UAAS+PPG group were respectively given L-cys, NaHS and PPG by intraperitoneal injection. The aorta was taken 6 weeks after surgery. Western blot was used to detect the activation of nPKCδ, the phosphorylation of Akt, and the expression of VCAM-1 in the aorta of mice. Results: The membrane translocation of nPKCδ in CHD patients with plaque was higher than that in CHD patients without plaque. The membrane translocation of nPKCδ and the expression of VCAM-1 in UAAS group was higher than sham group, L-cys or NaHS injection could suppress the membrane translocation of nPKCδ and the expression of VCAM-1, but PPG treatment resulted in more membrane translocation of nPKCδ and the expression of VCAM-1 (P<0.05, n=6 per group). Akt phosphorylation in UAAS group was lower than sham group, and L-cys or NaHS injection could suppress the degradation of Akt phosphorylation, but PPG treatment resulted in more decrease in the Akt phosphorylation (P<0.05, n=6 per group). Conclusion: Endogenous CSE/H2S system protected against the formation of UAAS via nPKCδ/Akt signal pathway. The imbalance of CSE/H2S system may participate in the formation of UAAS by affecting the expression of downstream molecule VCAM-1, which may be mediated by nPKCδ/Akt signaling pathway.
Highlights
Cardiovascular disease is the most common complication and leading cause of death in patients with chronic kidney disease, especially those on maintenance dialysis (Fishbane and Berns, 2005)
The incidence age of atherosclerosis in patients with endstage renal disease is advanced, and the disease progression is faster, which is known as uremia accelerated atherosclerosis (UAAS) (Sun et al, 2019)
Given the high-fat diet ApoE−/− mice supplement exogenous H2S donor sodium hydrosulfide (NaHS) could inhibit the progress of the blood vessel damage (Ford et al, 2013), lack of cystathionine-gamma-lyase (CSE), the key enzyme in generating H2S can lead to a variety of pathological changes such as vascular smooth muscle cells (VSMCs) proliferation (Yang et al, 2010), macrophages release TNF alpha (Wang et al, 2013)
Summary
Cardiovascular disease is the most common complication and leading cause of death in patients with chronic kidney disease, especially those on maintenance dialysis (Fishbane and Berns, 2005). Given the high-fat diet ApoE−/− mice supplement exogenous H2S donor sodium hydrosulfide (NaHS) could inhibit the progress of the blood vessel damage (Ford et al, 2013), lack of cystathionine-gamma-lyase (CSE), the key enzyme in generating H2S can lead to a variety of pathological changes such as vascular smooth muscle cells (VSMCs) proliferation (Yang et al, 2010), macrophages release TNF alpha (Wang et al, 2013). Cardiovascular disease is the most common complication and leading cause of death in maintenance hemodialysis patients. Previous studies have found that disorders of cystathionine-gamma-lyase/hydrogen sulfide (CSE/H2S) system in maintenance hemodialysis patients are correlated with the risk of cardiovascular disease. The role of CSE/H2S system in UAAS has been preliminarily explored, the molecular mechanism of CSE/H2S is still not systematically elaborated, and the molecular mechanism of nPKCδ and its related signaling pathway in UAAS is still not thoroughly studied
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