HSP70 inhibits stress-induced cardiomyocyte apoptosis by competitively binding to FAF1

Abstract

Stress-induced cardiomyocyte apoptosis plays an important role in the pathogenesis of a variety of cardiovascular diseases. Our early studies showed that HSP70 effectively inhibited apoptosis, but the underlying mechanism remained unclear. Fas-associated factor 1 (FAF1) is a member of the Fas death-inducing signaling complex (Fas-DISC) that acts upstream of caspase-8. We investigated the interactions among FAF1, HSP70, and FAS in stressed cardiomyocytes to elucidate the protective mechanism of HSP70. FAS and caspase-3/8 activity was higher in cardiomyocytes undergoing stress-induced apoptosis in restraint-stressed rats compared with cardiomyocytes in non-stressed rats, which indicated that the Fas signaling pathway was activated after restraint stress. Geranylgeranylacetone (GGA) induced an increase in HSP70 expression, which reduced stress-induced apoptosis. Additionally, overexpression of HSP70 via transfection with the pEGFP-rHSP70 plasmid attenuated norepinephrine (NE)-induced apoptosis. FAF1 expression increased during stressinduced apoptosis, and overexpression of FAF1 exacerbated NE-induced apoptosis. We also found that HSP70 interacted with FAF1. Overexpression of HSP70 inhibited the binding of FAF1 to FAS in H9C2 cells, which indicated that HSP70 suppressed NE-induced apoptosis by competitively binding to FAF1. An N-terminal deletion mutant of HSP70 (HSP70-△N) was unable to interact with FAF1. After HSP70-△N was transfected into H9C2 cells, the cells were unable to attenuate the NE-induced increases in caspase-8 and apoptosis. These results indicate that the 1-120 sequence of HSP70 binds to FAF1, which alters the interactions between FAS and FAF1 and inhibits the activation of the Fas signaling pathway and apoptosis.

The dissociation of the Hsp60/pro-Caspase-3 complex by bis(pyridyl)oxadiazole copper complex ( CubipyOXA ) leads to cell death in NCI-H292 cancer cells

“…Data obtained in the last decade indicate that Heat shock proteins (Hsps) have anti-apoptotic and, consequently, pro-tumor properties [29,30,31]. Apoptosis contributes to tumor demise following chemotherapy but, in patient management, it is still unclear how to achieve a healthy balance between cell proliferation and death [32].…”

“…However, the molecular mechanism of this anti-apoptotic effect mediated by Hsps is still unclear and it is possible that, under certain circumstances, may be due by a variety of different modulators [34]. It has been shown that Hsp70 can inhibit apoptosis by interacting with a member of the Fas death-inducing signaling upstream of Caspase-8 [37,38]. Hsp70, during oxidative stress, can stabilize Bcl-2, protecting the cell against apoptosis [39].…”

Effects of geranylgeranylacetone upon cardiovascular diseases

“…Cardiomyocyte apoptosis is one of the principal mechanisms for myocardial injury caused by various harmful factors . Recent studies have found that GGA protects the myocardium from physical or chemical stimuli, such as humid heat stress (HHS), psychologic stress, and toxic substances . In a mouse model of HHS, Wang et al found GGA pretreatment could enhance HSP70 expression under HHS and reverse the effect of HHS‐induced apoptosis by increasing expression of B‐cell lymphoma 2, decreasing levels of cytochrome c (Cyt c) in the cytosol but increasing levels of Cyt c in mitochondria.…”

“…Psychologic stress mainly targeting the cardiovascular system increases the risk of cardiovascular disease/complicated cardiovascular disease . It has been shown that GGA inhibits cardiomyocyte apoptosis induced by restraint stress, which is often used to study the influence of stress on physiologic functions and pathologic processes . GGA can inhibit activation of the Fas signaling pathway by inducing HSP70 expression.…”

“…GGA can inhibit activation of the Fas signaling pathway by inducing HSP70 expression. HSP70 bound to Fas‐associated factor 1 (FAF1), a member of the Fas death‐inducing signaling complex that acts upstream of caspase‐8, alters the interactions between FAS and FAF1, and inhibits the activation of the Fas signaling pathway and stress‐induced apoptosis …”