<p>Role of heat shock protein 22 in the protective effect of geranylgeranylacetone in response to oxidized-LDL</p>

Abstract

Objective The aim was to investigate the role and potential mechanism of geranylgeranylacetone (GGA) in the development of atherosclerosis, and to explore the role of heat shock protein 22 (HSP22) in mediating GGA effect. Methods Human coronary artery endothelial cell (HCAEC) was used for in vitro study. RNA interference was applied to suppress HSP22 in the cells. Cellular apoptosis and intracellular level of reactive oxygen species (ROS) were detected by flow cytometer, and proteins of HSP22, NF-κB, eNOS, and ICAM-1 were assessed by immunoblotting. HSP22 -/- //ApoE -/- , and HSP22 +/+ //ApoE -/- mice were used to investigate the effect of GGA in the animal model of atherosclerosis. Atherosclerotic lesion of the mice aortas was evaluated by Oil Red O staining and H&E staining. Results GGA significantly inhibited HCAEC apoptosis in response to oxidized-LDL (ox-LDL), but stimulated HSP22 synthesis in the cells. Transfection of HSP22-siRNA in the cells resulted in complete blockage of the GGA effect on apoptosis. GGA also significantly inhibited ROS, NF-κB, and ICAM-1 in the cells transfected control siRNA, but not in the cells transfected with HSP22-siRNA. Atherosclerotic plaque in the aorta was significantly less in the wild type (WT) animals treated with GGA as stained either by Oil Red O or by H&E staining, but not in the HSP22-KO mice. GGA significantly inhibited expression of NF-κB and ICAM-1 in the WT mice, but not in the HSP22-KO mice. Conclusion GGA-induced HSP22, and inhibited ox-LDL-induced apoptosis as well as expression of NF-κB and ICAM-1 in the HCAECs. GGA also attenuated formation of atherosclerotic plaques in mice aorta. Suppression of HSP22 by siRNA resulted in blockage of the GGA inhibition on apoptosis or stimulation on NF-κB and ICAM-1. These findings suggested that GGA protects endothelial cells from injury in response to ox-LDL and block atherosclerotic development in mice aorta through induction of HSP22.

Heat Shock Proteins in Oxidative Stress and Ischemia/Reperfusion Injury and Benefits from Physical Exercises: A Review to the Current Knowledge

“…The function of HSP in maintaining the oxidative-antioxidant balance seems to be multidirectional. Nowadays, the effect of HSP on OS has been considered in the aspect of cellular homeostasis [ 40 ], atherosclerosis/oxLDL (oxidized low-density lipoproteins) [ 41 ], pollution [ 42 ], hearing loss [ 43 ], and many others. Interestingly, HSPs have been reported to work hand in hand with the antioxidant system to inhibit or neutralize the cellular effects of ROS [ 44 ].…”

The Role of HSPB8, a Component of the Chaperone-Assisted Selective Autophagy Machinery, in Cancer

“…Other HSPB8 inducers are the compounds able to mount the stress response mediated by the activation of HSF1, the key master regulator of HSP family gene expression. Among these are the HSPs inducer geranylgeranylacetone (GGA) [ 139 , 140 ] and the potent HSPs inducer multitarget small molecule N -((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)- N -methylprop-2-yn-1-amine (ASS234) [ 141 ]. Both molecules have been successfully tested on AD models [ 142 , 143 , 144 , 145 , 146 , 147 ], exerting a protective role mediated by HSPs in general, and especially by HSPB8.…”

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

“…HSPs provide cardioprotection by preventing the accumulation of misfolded proteins, inhibiting myocardial cell death pathways, regulating ion channels, and impeding the function of pro-inflammatory cytokines [13]. Moreover, the importance of HSPs in heart function is highlighted in studies showing the protective effects of HSP-inducing therapeutics during cardiovascular diseases [14][15][16][17][18].…”

“…Cells 2021, 10, x FOR PEER REVIEW 3 of impeding the function of pro-inflammatory cytokines [13]. Moreover, the importance o HSPs in heart function is highlighted in studies showing the protective effects of HSP inducing therapeutics during cardiovascular diseases [14][15][16][17][18].…”