Cardiac Protective Role of Heat Shock Protein 27 in the Stress Induced by Drugs of Abuse

Elena Martínez-Laorden,Pilar Almela,María Luisa Laorden,Javier Navarro-Zaragoza,María Victoria Milanés

doi:10.3390/ijms21103623

Elena Martínez-Laorden, Pilar Almela + Show 3 more

Open Access

https://doi.org/10.3390/ijms21103623

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Abstract

Heat shock proteins (HSP) are induced after different stress situations. Some of these proteins, particularly HSP-27, function as markers to indicate cellular stress or damage and protect the heart during addictive processes. Morphine withdrawal induces an enhancement of sympathetic activity in parallel with an increased HSP-27 expression and phosphorylation, indicating a severe situation of stress. HSP-27 can interact with different intracellular signaling pathways. Propranolol and SL-327 were able to antagonize the activation of hypothalamic-pituitary adrenal (HPA) axis and the phosphorylation of HSP-27 observed during morphine withdrawal. Therefore, β-adrenergic receptors and the extracellular signal-regulated kinase (ERK) pathway would be involved in HPA axis activity, and consequently, in HSP-27 activation. Finally, selective blockade of corticotrophin releasing factor (CRF)-1 receptor and the genetic deletion of CRF1 receptors antagonize cardiac adaptive changes. These changes are increased noradrenaline (NA) turnover, HPA axis activation and decreased HSP-27 expression and phosphorylation. This suggests a link between the HPA axis and HSP-27. On the other hand, morphine withdrawal increases µ-calpain expression, which in turn degrades cardiac troponin T (cTnT). This fact, together with a co-localization between cTnT and HSP-27, suggests that this chaperone avoids the degradation of cTnT by µ-calpain, correcting the cardiac contractility abnormalities observed during addictive processes. The aim of our research is to review the possible role of HSP-27 in the cardiac changes observed during morphine withdrawal and to understand the mechanisms implicated in its cardiac protective functions.

Highlights

Stress proteins are classified into five families based on their amino acid sequence and molecular weight: 1) low molecular weight (15–30 kDa), 2) 60 kDa, 3) 70 kDa, 4) 90 kDa, and 5) high molecular weight (100–110 kDa) [1]
This stabilization seems to be an action caused by the non-phosphorylated form, which is responsible for the Heat shock proteins (HSP) activity as a molecular chaperone [21,22], and participates in the solubilization of the aggregates of denatured proteins after stress [23]
During the morphine withdrawal syndrome, there is an increase in cardiac troponin T expression together with a decrease in cardiac troponin I expression, and a co-localization between cTnT and Heat Shock Protein 27 (HSP-27) which has been described by immunofluorescence [75]. These results indicate that HSP-27 could protect cTnT from protease degradation and from proteolysis by μ-calpain, whose expression is increased during withdrawal symptoms

Summary

Introduction

Stress proteins are classified into five families based on their amino acid sequence and molecular weight: 1) low molecular weight (15–30 kDa), 2) 60 kDa, 3) 70 kDa, 4) 90 kDa, and 5) high molecular weight (100–110 kDa) [1]. The stabilization of actin filaments occurs thanks to the different phosphorylation/dephosphorylation processes, which prevent the degradation and depolymerization induced by oxidative damage or thermal shock [20] This stabilization seems to be an action caused by the non-phosphorylated form, which is responsible for the HSP activity as a molecular chaperone [21,22], and participates in the solubilization of the aggregates of denatured proteins after stress [23]. Together with the enhancement of sympathetic activity, drugs of abuse and withdrawal induce an increased HSP-27 expression and phosphorylation This enhancement suggests that this chaperone protects the heart against the cardiac changes observed after binge ethanol associated to methylenedioxymethamphetamine, methamphetamine and their withdrawals. They supply information about potential targets for the development of novel and effective pharmacotherapies to reduce cardiovascular- and stress-related complications associated with drugs of abuse

Morphine Addiction and HSP-27

Conclusions and Future Perspective