HSP22 suppresses diabetes-induced endothelial injury by inhibiting mitochondrial reactive oxygen species formation

Abstract

The induction of mitochondrial reactive oxygen species (mtROS) by hyperglycemia is a key event responsible for endothelial activation and injury. Heat shock protein 22 (HSP22) is a stress-inducible protein associated with cytoprotection and apoptosis inhibition. However, whether HSP22 prevents hyperglycemia-induced vascular endothelial injury remains unclear. Here, we investigated whether HSP22 protects the vascular endothelium from hyperglycemia-induced injury by reducing mtROS production. We used a high-fat diet and streptozotocin injection model to induce type 2 diabetes mellitus (T2DM, metabolic syndrome) and exposed human umbilical vein endothelial cells (HUVECs) to high glucose following overexpression or silencing of HSP22 to explore the role of HSP22. We found that HSP22 markedly inhibited endothelial cell activation and vascular lesions by inhibiting endothelial adhesion and decreasing cytokine secretion. We performed confocal microscopy and flow cytometry assays using HUVECs and showed that HSP22 attenuated mtROS and mitochondrial dysfunction in hyperglycemia-stimulated endothelial cells. Mechanistically, using the mtROS inhibitor MitoTEMPO, we demonstrated that HSP22 suppressed endothelial activation and injury by eliminating hyperglycemia-mediated increases in mtROS. Furthermore, we found that HSP22 maintained the balance of mitochondrial fusion and fission by mitigating mtROS in vitro. HSP22 attenuated the development of vascular lesions by suppressing mtROS-mediated endothelial activation in a T2DM mouse model. This study provides evidence that HSP22 may be a promising therapeutic target for vascular complications in T2DM.

Heat shock protein 22 modulates NRF1/TFAM-dependent mitochondrial biogenesis and DRP1-sparked mitochondrial apoptosis through AMPK-PGC1α signaling pathway to alleviate the early brain injury of subarachnoid hemorrhage in rats

“…HSP22, a small heat shock protein, has recently been reported to have beneficial properties against oxidative stress [ 16 , 18 ], mitochondrial dysfunction [ 20 ], endothelial injury [ 19 ], aging [ 14 ] and apoptosis [ 32 ]. Concretely, an in vitro study showed that overexpression of hsp22 markedly restrained H 2 O 2 -induced hippocampal neuronal cell death by modulation of the mitochondrial-related apoptosis pathway [ 20 ].…”

“…Heat shock protein 22 (Hsp22), also called H11 Kinase and HSPB8, is a small heat shock protein and originally as a necessity for the growth of Drosophila melanogaster [ 14 , 15 ], has recently been demonstrated to have the properties of mitochondria-protection, anti-oxidation, anti-apoptosis in myocardial injury [ 16 ], cerebral ischemia [ 17 ] and aging [ 18 ]. Notably, hsp22 treatment could maintain the balance of mitochondrial fusion and fission to mitigate mitochondria-derived ROS [ 19 ]. Additionally, forceful proofs demonstrated that overexpression of hsp22 markedly attenuates oxidative stress-induced hippocampal neuronal cell death through the suppression of mitochondria-mediated apoptosis cascade responses [ 20 ].…”

The transcriptome-wide association search for genes and genetic variants which associate with BMI and gestational weight gain in women with type 1 diabetes

“…ATP5G3 is involved in the proton pathway and acts as an energy-driving motor (Huang et al 2013 ; He et al 2017 ; Spataru et al 2019 ). HSPB8 is known to prevent oxidative tissue damage and its expression in serum is used as a biomarker for virus induced type 1 diabetes (Karthik et al 2012 ; Li et al 2017 ; Yu et al 2019 ). We also identified rs34427781—an eQTL for several genes ( CYP2D8P, NDUFA6-AS1, CYP2D6, CCDC134, CENPM, CHADL, FAM109B, NAGA, NDUFA6, OGFRP1, OLA1P1, SEPT3, SHISA8, SLC25A5P1, SMDT1, SREBF2, TNFRSF13C, WBP2NL )—to be associated with BMI.…”

“The transcriptome-wide association search for genes and genetic variants which associate with BMI and gestational weight gain in women with type 1 diabetes”

“…ATP5G3 is involved in the proton pathway and acts as an energy-driving motor (He et al, 2017; Huang et al, 2013; Spataru, Le Duc, Zagrean, & Zagrean, 2019). HSPB8 is known to prevent oxidative tissue damage and its expression in serum is used as a biomarker for virus induced type 1 diabetes (Karthik, Ilavenil, Kaleeswaran, Sunil, & Ravikumar, 2012; X. C. Li et al, 2017; L. Yu et al, 2019). We also identified rs34427781 - an eQTL for several genes ( CYP2D8P, NDUFA6-AS1, CYP2D6, CCDC134, CENPM, CHADL, FAM109B, NAGA, NDUFA6, OGFRP1, OLA1P1, SEPT3, SHISA8, SLC25A5P1, SMDT1, SREBF2, TNFRSF13C, WBP2NL ) to be associated with BMI.…”