c-Jun N-Terminal Kinases (JNKs) in Myocardial and Cerebral Ischemia/Reperfusion Injury

Abstract

In this article, we review the literature regarding the role of c-Jun N-terminal kinases (JNKs) in cerebral and myocardial ischemia/reperfusion injury. Numerous studies demonstrate that JNK-mediated signaling pathways play an essential role in cerebral and myocardial ischemia/reperfusion injury. JNK-associated mechanisms are involved in preconditioning and post-conditioning of the heart and the brain. The literature and our own studies suggest that JNK inhibitors may exert cardioprotective and neuroprotective properties. The effects of modulating the JNK-depending pathways in the brain and the heart are reviewed. Cardioprotective and neuroprotective mechanisms of JNK inhibitors are discussed in detail including synthetic small molecule inhibitors (AS601245, SP600125, IQ-1S, and SR-3306), ion channel inhibitor GsMTx4, JNK-interacting proteins, inhibitors of mixed-lineage kinase (MLK) and MLK-interacting proteins, inhibitors of glutamate receptors, nitric oxide (NO) donors, and anesthetics. The role of JNKs in ischemia/reperfusion injury of the heart in diabetes mellitus is discussed in the context of comorbidities. According to reviewed literature, JNKs represent promising therapeutic targets for protection of the brain and the heart against ischemic stroke and myocardial infarction, respectively. However, different members of the JNK family exert diverse physiological properties which may not allow for systemic administration of non-specific JNK inhibitors for therapeutic purposes. Currently available candidate JNK inhibitors with high therapeutic potential are identified. The further search for selective JNK3 inhibitors remains an important task.

Targeting autophagy in cardiac ischemia/reperfusion injury: A novel therapeutic strategy

“…They identified that miR-410 suppressed high-mobility group box 1 protein (HMGB1) so that transfection of cardiomyocytes with pcDNA3.1-HMGB1 promoted autophagy, reduced apoptosis, and improved mitochondria function by modulating heat shock protein β1 (Yang, Li, Dong, & Mi, 2018). Moreover, HMGB1 in collaboration with the TNF promoted apoptosis of cardiomyocytes under I/R by JNK activation (Shvedova, Anfinogenova, Atochina-Vasserman, Schepetkin, & Atochin, 2018). miR-30e is another miRNA involved in I/R injury through autophagy, which was downregulated in patients with myocardial I/R injury.…”

PDRPS7 protects cardiac cells from hypoxia/reoxygenation injury through inactivation of JNKs

“…These findings suggest that JNK inactivation may be involved in the cellular protection of PDRPS7. JNKs belong to a family of MAPKs, which are activated in response to various stress stimuli such as ultraviolet radiation, oxidative stress, heat and osmotic shock, and cardiac I/R injury . In addition, JNK signaling pathway has been shown to play critical roles in regulating cell fate, being implicated in a multitude of diseases ranging from cancer to ischemic immunological/inflammatory conditions .…”

“…JNKs belong to a family of MAPKs, which are activated in response to various stress stimuli such as ultraviolet radiation, oxidative stress, heat and osmotic shock, and cardiac I/R injury . In addition, JNK signaling pathway has been shown to play critical roles in regulating cell fate, being implicated in a multitude of diseases ranging from cancer to ischemic immunological/inflammatory conditions . JNKs cause changes to gene transcription, resulting in biological responses such as inflammation and/or apoptosis .…”

“…In addition, JNK signaling pathway has been shown to play critical roles in regulating cell fate, being implicated in a multitude of diseases ranging from cancer to ischemic immunological/inflammatory conditions . JNKs cause changes to gene transcription, resulting in biological responses such as inflammation and/or apoptosis . Many effects of JNKs are mediated by transcription factors of the activator protein‐1 family, of which c‐Jun is the most commonly known.…”

“…ERK activation has been shown to protect the heart against I/R injury by modulating pro‐apoptotic and prosurvival signaling . However, numerous studies have demonstrated that JNKs‐ and p38‐mediated signaling pathways play an essential role in myocardial I/R injury . Indeed, p38 and JNK inhibition using either genetic modulation or chemical inhibitors protects cardiomyocytes against I/R injury .…”