Molecular Chaperone HSP70 and Key Regulators of Apoptosis - A Review

Identified as a molecular chaperone constitutively being synthesized due to enhanced elevated temperature change, this heat shock protein HSP70 has shown to be intimately involved in many protein biogenesis, facilitating the synthesis and folding of proteins and trafficking of nascent peptides during cell growth. HSP70 also plays a vital role in protein assembly, regulation and interaction with a wide variety of proteins. Stress-induced cell death is under the control of the Bcl-2 family of apoptotic regulators and display either pro-apoptotic or anti-apoptotic activities. Subjected to stress conditions such as heat shock, cells have been reported to express elevated expressions of HSP70. Moreover, this molecular chaperon has shown to act at multiple levels to suppress stressed-induced apoptotic signals of some Bcl-2 members by repairing, re-synthesizing damaged proteins, and stabilizing unfolded proteins. Therefore, HSP70 synthesis can act as an essential recovery mode for cellular survival and adaptation during lethal conditions.

Yi-Zhi-Fang-Dai Formula Protects against Aβ1–42Oligomer Induced Cell Damage via Increasing Hsp70 and Grp78 Expression in SH-SY5Y Cells

Yi-Zhi-Fang-Dai formula (YZFDF) is an experiential prescription used to cure dementia cases like Alzheimer’s disease (AD). In this study, the main effective compounds of YZFDF have been identified from this formula, and the neuroprotective effect againstAβ1–42oligomer of YZFDF has been tested in SH-SY5Y cells. Our results showed that YZFDF could increase cell viability and could attenuate endothelial reticula- (ER-) mediated apoptosis. Evidence indicated that protein folding and endothelial reticula stress (ERS) played an important role in the AD pathological mechanism. We further explored the expression of Hsp70, an important molecular chaperon facilitating the folding of other proteins, and Grp78, the marker protein of ERS in SH-SY5Y cells. Data told us that YZFDF pretreatment could influence the mRNA and protein expression of these two proteins. At last, we also found that YZFDF pretreatment could activate Akt in SH-SY5Y cells. All these above indicate that YZFDF could be a potent therapeutic candidate for AD treatment.

Abstract 19822: Arterial Calcification Can Be Inhibited via Stress Protein Induction Through a PPAR-dependent Pathway

Introduction: Cardiovascular disease occurs prematurely in chronic inflammatory conditions such as Chronic Kidney Disease (CKD) and unfortunately, remains the leading cause of death in these patients. Vascular calcification (VC) is a significant contributor to cardiovascular mortality in CKD patients with the sequela of arterial hardening, congestive heart failure and sudden cardiac death. We recently reported that heat shock protein 72 (HSP72) when inducted, can inhibit the development of VC. Hypothesis: We hypothesize that HSP72 exerts its vasculo-protective effects by functioning as a molecular chaperon for peroxisome proliferator-activated receptor γ (PPARγ). Methods: We developed an in vitro long-term calcification model using HA-SMCs treated with calcification medium (CM) containing 5mM CaCl2 and 5mM β-glycerophosphate for 21 days. Cells were subjected to heat shock treatment at 43°C for 30 minutes daily to induce HSP72. Calcification was assessed qualitatively by alizarin red staining and quantitatively by the arsenazo III method. Results: Our results show that inducible HSP72 is significantly expressed following heat shock treatment in HA-SMCs. Induction of HSP72 inhibited the development of VC in our long-term calcification model and these effects were abolished by HSP72 siRNA, in vitro. We next showed that HSP72 formed a protein-protein complex with PPARγ by co-immunoprecipitation. Expression of both these proteins was down-regulated in calcific HA-SMCs and their gene expression was down regulated in atherosclerotic human arteries. Furthermore, we found that the PPARγ inhibitor, FABP4 (fatty acid binding protein-4) which function as an atherosclerosis promoter was up-regulated in calcified human arteries. Lastly, induction of HSP72 restored expression of the HSP72-PPARγ complex and inhibited upregulation of FABP4 with reduction in calcification in our in vitro calcification model. These vasculo-protective effects were abolished by HSP72 siRNA. Conclusion: HSP72 is a powerful inhibitor of VC and exerts its vasculo-protective effects by functioning as a molecular chaperon to stabilize PPARγ and regulate the PPARγ-FABP4 pathway. We suggest treatment strategies involving induction of HSP72 as a new approach to inhibit VC.