Heat shock protein 70: A promising therapeutic target for myocardial ischemia–reperfusion injury

Abstract

Acute myocardial infarction is a major cause of death worldwide. The most important therapy for limiting ischemic injury and infarct size is timely and efficient myocardial reperfusion treatment, which may instead induce cardiomyocyte necrosis due to myocardial ischemia-reperfusion (I/R) injury. Heat shock protein 70 (HSP70), a stress-inducible protein, is overexpressed during myocardial I/R. The induced HSP70 is shown to regulate several intracellular proteins (e.g., transcription factors, enzymes, and apoptosis-related proteins) and signaling pathways (e.g., c-Jun N-terminal kinase pathway and extracellular-signal-regulated kinase 1/2 pathway), forming a complicated network that contributes to reducing reactive oxygen species accumulation, improving calcium homeostasis, inhibiting cellular apoptosis, thereby enhancing the stress adaption of myocardium to I/R injury. In addition, the extracellular HSP70, which is released from injured cardiomyocytes during I/R, acts as a proinflammatory mediator that results in cell death, while the intracellular HSP70 exerts antiinflammatory effects by suppressing proinflammatory signaling pathways. Notably, HSP70 is induced and contributes to the cardioprotection in several types of preconditioning and postconditioning. Meanwhile, it is shown that the cardioprotective effectiveness of preconditioning-induced HSP70 (e.g., hyperthermia preconditioning-induced HSP70) can be impaired by certain pathological conditions, such as hyperlipidemia and hyperglycemia. Thus, we highlight the widespread cardioprotective involvement of HSP70 in preconditioning and postconditioning and elucidate how HSP70-mediated cardioprotection is impaired in these pathological conditions. Furthermore, several therapeutic potentials of HSP70 against myocardial I/R injury and potential directions for future studies are also provided in this review.

Come Together: Protein Assemblies, Aggregates and the Sarcostat at the Heart of Cardiac Myocyte Homeostasis

“…Transgenic expression of Hsp70 or its interacting protein CHIP (Carboxyl terminus of Hsp70-interacting protein (CHIP), a ubiquitin ligase) was protective against doxorubicin-induced cardiomyopathy (Naka et al, 2014;Wang et al, 2016). Furthermore, an aggregate of studies suggest that activation of Hsp70 signaling in protective against cardiac ischemia-reperfusion injury (Song et al, 2019). However, a note of caution is relevant given a role for Hsp70 described in promoting cardiac hypertrophy in response to pressure overload, which is typically pathologic and results in decompensation (Kee et al, 2008).…”

The Role of O-GlcNAcylation for Protection against Ischemia-Reperfusion Injury

“…Elevating O-GlcNAc levels augments expression of HSPs by heat stress [14,95], while decreasing O-GlcNAc suppresses expression of HSPs [96]. Expression of HSP70 and HSP72 may be protective against IR injury through repression of apoptosis [97,98,99], because they are upregulated by a RIC stimulus [100]. Jones et al showed that HSP70 levels were increased in cardiomyocytes that were protected by PUGNAc against H 2 O 2 injury [20].…”

Proteomic analysis identifies plasma correlates of remote ischemic conditioning in the context of experimental traumatic brain injury

“…Members of the heat shock protein 70 family and have also been linked to cancer and multiple neurodegenerative diseases 37 . Overexpression of HSP70 suppressed ischemia–reperfusion damage, as well as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease 38 – 40 . One study found that HSPA8 functions as a safeguard for protein homeostasis and is reduced in brains of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease 41 .…”

“…Of these, 243 proteins were shared between all 4 groups (Fig. 3A), whereas ~ 8% (38) and ~ 12% (57) were unique to TBI and TBI RIC groups, respectively. Pathway analysis based on the entire proteome revealed 63 uniquely enriched pathways, 46 (73%) of which were shared across all conditions ( Fig.…”

“…This analysis identified 493 unique proteins across all four groups. Of these, 243 proteins were shared between brain injury and treatment groups, whereas ~ 7.7%(38) and ~ 11.5% (57) were unique to TBI and TBI RIC groups, respectively. (B) Barplot showing the number of proteins mapped to enriched pathways from TBI RIC (black bars) and TBI (white bars) conditions.…”