ATP2B1 gene Silencing Increases Insulin Sensitivity through Facilitating Akt Activation via the Ca²⁺/calmodulin Signaling Pathway and Ca²⁺-associated eNOS Activation in Endothelial Cells

Abstract

Endothelial cell insulin resistance may be partially responsible for the higher risk of atherosclerosis and cardiovascular disease in populations with insulin resistance and type 2 diabetes mellitus (T2DM). A genome-wide association study revealed a significant association between the ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) gene and T2DM in two community-based cohorts from the Korea Association Resource Project. However, little is known about the implication of the ATP2B1 gene on T2DM. In the present study, we investigated the role of the ATP2B1 gene in endothelial cell insulin sensitivity. ATP2B1 gene silencing resulted in enhanced intracellular calcium concentrations and increased insulin-induced Akt activation compared to that in the negative siRNA-transfected HUVECs (Human Umbilical Vein Endothelial Cells). The elevated insulin sensitivity mediated by ATP2B1 gene silencing was Ca2+/calmodulin-dependent, as verified by administration of the calcium chelator BAPTA-AM or the calmodulin-specific antagonist W7. Moreover, higher levels of phosphorylation of eNOS (Ser1177) were observed in ATP2B1-silenced HUVECs. In addition to BAPTA-AM and W7, L-NAME, an eNOS antagonist, abolished insulin-induced Akt phosphorylation at Ser473 in both si-Neg and si-ATP2B1-transfected endothelial cells. These results indicate that the enhanced insulin sensitivity in ATP2B1-silenced endothelial cells is alternatively dependent on an increase in intracellular Ca2+ and the subsequent activation of the Ca2+/calmodulin/eNOS/Akt signaling pathway. In summary, ATP2B1 gene silencing increased insulin sensitivity in endothelial cells by directly modulating the Ca2+/calmodulin signaling pathway and via the Ca2+/calmodulin/eNOS/Akt signaling pathway alternatively.

Lactobacillus plantarumTWK10‐fermented soymilk improves cognitive function in type 2 diabetic rats

“…30,31 In addition, eNOS is a Ca 2+ /CaM-dependent enzyme and is responsible for NO generation, which subsequently exhibits anti-oxidative, anti-inflammatory, and vascular regulatory activities. 32 The data presented in this study shows that the CaM levels and NO concentration were significantly decreased in the DC rats (P < 0.05). In agreement with the results of previous studies, long-term STZ-induced diabetes was found to cause a significant decrease in CaM levels in the aortic tissues and disrupted the balance between NO and ROS.…”

“…In agreement with the results of previous studies, long-term STZ-induced diabetes was found to cause a significant decrease in CaM levels in the aortic tissues and disrupted the balance between NO and ROS. 32 Moreover, Long et al reported that the Ca 2+ /CaM/eNOS signaling pathway could enhance insulin sensitivity. [32][33][34] Xi and coworkers.…”

“…32 Moreover, Long et al reported that the Ca 2+ /CaM/eNOS signaling pathway could enhance insulin sensitivity. [32][33][34] Xi and coworkers. found that the CaM, CaMKII/pCaMKII, and CREB/pCREB protein expression levels were downregulated after amyloid-beta administration and that genistein could reverse this altered expression.…”

The Inhibitory Effects of Gold Nanoparticles on VEGF-A-Induced Cell Migration in Choroid-Retina Endothelial Cells

“…The PI3K/Akt pathway provides essential signaling for cell survival and proliferation. Signaling from different eNOS agonists, such as VEGF, insulin, and estrogen can affect eNOS activity through the PI3K/AKT pathway [47][48][49]. It has been reported that activations of the survival signal PI3K/Akt pathway and the endothelial-specific eNOS/NO pathway were closely associated with vascular remodeling and angiogenesis [50,51].…”

Variability of Selected Genes in Relation to the Parameters of Bones in Laying Hens: A Pilot Study

“…The plasma membrane calcium pump (PMCA) plays an important role in cellular calcium homeostasis (Ryan et al, 2015). The ATP2B1 gene, in hens located on chromosome 1, region 43 273 706-43 305 815 bp, encodes plasma membrane calcium ATPase 1 (PMCA1) (Horecka et al, 2015;Long et al, 2017, Horecka et al, 2018. Because most of studying proteins are involved in osteogenesis, bone remodelling and process of calcium metabolism, so polymorphisms of genes, encoding selected proteins, may play an important role in the pathogenesis of osteoporosis, by influencing protein formation and consequently bone formation.…”