Sestrin2 Is Increased in Calcific Aortic Disease and Inhibits Osteoblastic Differentiation in Valvular Interstitial Cells via the Nuclear Factor E2–related Factor 2 Pathway

Abstract

Sestrin2 (Sesn2) is involved in the progression of cardiovascular diseases, such as hypertension and myocardial infarction. This study aimed to examine Sesn2 expression in human calcific aortic valve disease (CAVD) and explore its possible mechanisms by which Sesn2 participates in this process. CAVD and normal aortic valves were collected. Sesn2 expression and sources were examined, and the results showed that Sesn2 expression was increased in aortic valves from patients with CAVD and was mainly secreted by macrophages. Additionally, U937 macrophages were pretreated with si-Sesn2 or cDNA-Sesn2 and further treated with oxidized low-density lipoprotein (ox-LDL); M1 macrophages and their markers were measured, and we found that pretreatment with si-Sesn2 increased ox-LDL-induced M1 macrophage polarization and marker mRNA levels, whereas pretreatment with cDNA-Sesn2 had the opposite effects. In ox-LDLtreated U937 macrophages, oxidative stress levels were increased in the si-Sesn2 pretreatment group and further increased by si-Nrf2 treatment, whereas oxidative stress levels were decreased in the cDNA-Sesn2 pretreatment group and significantly reversed by ML385, a specific Nrf2 inhibitor. The effects of Sesn2 on ox-LDL-induced oxidative stress and the osteogenic differentiation of ox-LDL-induced valvular interstitial cells (VICs) was examined by down-regulating Nrf2 pathway. When U937 macrophages were co-cultured with VICs, downregulation of Sesn2 increased ox-LDL-induced osteogenic differentiation in VICs, whereas overexpression of Sesn2 exerted the opposite effects. Our study suggests that Sesn2 is increased in CAVD aortic valves and may participate in the development of CAVD by regulating oxidative stress via the Nrf2 pathway.

The impact of sestrin2 on reactive oxygen species in diabetic retinopathy

“…Rh‐sestrin2 treatment also decreased the HUVEC cells tube formation activity and declined VEGF, TNF‐α, and IL‐1β contents. Previous studies confirmed that sestrin2 enhanced cell viability and proliferation by protecting against oxidative stress and cell apoptosis 26,27 . Our results were similar to their results.…”

“…Previous studies confirmed that sestrin2 enhanced cell viability and proliferation by protecting against oxidative stress and cell apoptosis. 26,27 Our results were similar to their results.…”

Muscular Sestrins: Roles in Exercise Physiology and Stress Resistance

“…Sestrin2 expression declines with age in mice, which is associated with increased susceptibility to myocardial injury [43]. Circulating Sestrin levels were elevated in human patients with hypertension [44], permanent atrial fibrillation [45], calcific aortic disease [46], and coronary heart diseases [47,48], suggesting the general association of Sestrins with cardiovascular diseases. Taking these results together, we can say that cardiovascular stress and pathologies are generally associated with increased Sestrin expression, while the development of chronic pathologies in certain contexts are associated with the downregulation of Sestrins, which further exacerbates the pathologies.…”

Sestrin2 in diabetes and diabetic complications

“…In turn, Sestrin2 can function as a positive regulator of Nrf2 signaling, activate the Nrf2 pathway by augmenting autophagy-directed degradation of Keap1, which targets and breaks down Nrf2 ( 6 , 53 ). Sestrin2 overexpression suppresses oxidative stress and cell apoptosis by activating Nrf2-ARE signaling ( 54 , 55 ). Also, Sestrin2/Nrf2 signaling may be important for the mediation of ER stress as a downstream regulator of the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway ( 56 ), which is illustrated below.…”