Salusin‐β Is Involved in Diabetes Mellitus‐Induced Endothelial Dysfunction via Degradation of Peroxisome Proliferator‐Activated Receptor Gamma

Abstract

The pathophysiological mechanisms for vascular lesions in diabetes mellitus (DM) are complex, among which endothelial dysfunction plays a vital role. Therapeutic target against endothelial injury may provide critical venues for treatment of diabetic vascular diseases. We recently identified that salusin-β contributed to high glucose-induced endothelial cell apoptosis. However, the roles of salusin-β in DM-induced endothelial dysfunction remain largely elusive. Male C57BL/6J mice were used to induce type 2 diabetes mellitus (T2DM) model. Human umbilical vein endothelial cells (HUVECs) were cultured in high glucose/high fat (HG/HF) medium. We demonstrated increased expression of salusin-β in diabetic aortic tissues and high-glucose/high-fat- (HG/HF-) incubated HUVECs. Disruption of salusin-β by shRNA abrogated the reactive oxygen species (ROS) production, inflammation, and nitrotyrosine content of HUVECs cultured in HG/HF medium. The HG/HF-mediated decrease in peroxisome proliferator-activated receptor γ (PPARγ) expression was restored by salusin-β shRNA, and PPARγ inhibitor T0070907 abolished the protective actions of salusin-β shRNA on endothelial injury in HG/HF-treated HUVECs. Salusin-β silencing obviously improved endothelium-dependent vasorelaxation, oxidative stress, inflammatory response, and nitrative stress in diabetic aorta. Taken together, our results highlighted the essential role of salusin-β in pathological endothelial dysfunction, and salusin-β may be a promising target in treatment of vascular complications of DM.

Salusin-β mediates tubular cell apoptosis in acute kidney injury: Involvement of the PKC/ROS signaling pathway

“…The superoxide anions-mediated renal tubules damage may be an important contributor to the progression of AKI [51]. In light of oxidative stress, salusin-β is recently proposed as an oxidation inducer in brain tissues, VSMCs and endothelial cells in multiple disease scenarios [23,28,52]. Therefore, we wanted to determine whether salusin-β knockdown or overexpression altered cisplatin-induced oxidative stress in renal tubular cells.…”

Stimulation of Na+/K+-ATPase with an Antibody against Its 4thExtracellular Region Attenuates Angiotensin II-Induced H9c2 Cardiomyocyte Hypertrophy via an AMPK/SIRT3/PPARγSignaling Pathway

“…Immunofluorescent staining was performed as described previously [24]. The collected H9c2 cardiomyocytes or primary neonatal mouse cardiomyocytes were fixed in freshly made -20°C ethanol at room temperature for 10 min and then permeabilized with 0.1% Triton X-100.…”

Improvement of Vascular Function by Knockdown of Salusin-β in Hypertensive Rats via Nitric Oxide and Reactive Oxygen Species Signaling Pathway

“…These results suggest that the interference of salusin-β gene expression improves endotheliumdependent vasodilation, decreases vascular constriction and blood pressure, and repairs vascular remodeling of SHR by decreasing NAD(P)H oxidase generated ROS production and increasing eNOS activation to release NO. It has been reported that salusin-β promotes the inflammatory response of human umbilical vein ECs (Karin and Delhase, 2000;Zhao et al, 2017), causes endothelial injury and dysfunction in diabetes mellitus (Sun et al, 2017;Zhu et al, 2017), and promotes the proliferation, migration and foam cell formation of VSMCs (Sun et al, 2015;Sun et al, 2016a,b). Intravenous administration of salusin-β in rats increases ABP, and overexpression of salusinβ in rats causes persistent elevation of blood pressure (Sun et al, 2015).…”

“…Intravenous administration of salusin-β in rats increases ABP, and overexpression of salusinβ in rats causes persistent elevation of blood pressure (Sun et al, 2015). As the exact natural receptor of salusin-β has not yet been found, gene silencing of salusin-β by shRNA is a good way to detect the effects of endogenous salusin-β (Sun et al, 2017). In the study, we found that after knockdown of salusin-β gene expression in rats, the SBP, DBP, and HR, especially DBP, of SHR decreased significantly.…”

“…The previous studies have found that delivery of salusin-β to either the central paraventricular nucleus or rostral ventrolateral medulla increased renal sympathetic nerve activity, arterial blood pressure (ABP), and heart rate (HR) in rats (Chen et al, 2013;Sun et al, 2014;Li et al, 2015b;Xie et al, 2017). In addition, salusin-β causes endothelial dysfunction and injury in diabetes mellitus (Sun et al, 2017;Zhao et al, 2017) and provokes the NAD(P)H oxidase derived-reactive oxygen species (ROS) production in human umbilical vein ECs (Panieri and Santoro, 2015;Sag et al, 2017;Yin et al, 2017;Esfahani et al, 2018). However, the effects of silencing salusin-β expression on vascular function in primary hypertensive rats remain unexplored.…”