Pak2 Regulation of Nrf2 Serves as a Novel Signaling Nexus Linking ER Stress Response and Oxidative Stress in the Heart

Binder, Pablo; Nguyen, Binh; Collins, Lucy; Zi, Min; Liu, Wei; Christou, Foteini; Luo, Xue‐Gang; Hille, Susanne; Frey, Norbert; Cartwright, Elizabeth J.; Chernoff, Jonathan; Müller, Oliver; Guan, Kaomei; Wang, Xin

doi:10.3389/fcvm.2022.851419

Cited by 20 publications

(17 citation statements)

References 49 publications

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“…Additionally, NO produced by endothelial NO synthase (eNOS) plays a role in the regulation of cell growth, apoptosis, and tissue perfusion (Dimmeler et al ., 1997) and our findings of apoptosis and downregulation of NOS corroborates early findings (Feng et al ., 2002). ER stress and oxidative stress have been highly implicated in many cardiac pathologies (Binder et al ., 2022) (Dhalla et al ., 2000) including the pathogenesis of AF (Li et al ., 2010). Recent studies highlight the importance of PAK2.…”

Section: Discussionmentioning

confidence: 99%

Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation

Ayagama

Charles

Bose

et al. 2023

Preprint

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Endolysosomes (EL) are known for their role in regulating both intracellular trafficking and proteostasis. EL help facilitate elimination of damaged membrane and cytosolic proteins, protein aggregates, membranous organelles and also play an important role in calcium signalling. Despite the importance of EL, their specific role in cardiovascular disease is not well understood. In particular, it's unclear how EL contribute to atrial pathology over longer time frames. To shed light on this question, we conducted a comprehensive analysis that involved proteomics, transcriptomics, integrated analysis, electron tomography, western blotting, and enzyme assays. To identify the role of EL in atrial fibrillation (AF), we applied a recently published organelle protein isolation method. We used this method to study biopsies from AF goat model and analyse the EL-specific proteins and pathways involved in this condition. Our results revealed the upregulation of the AMPK pathway and the expression of EL-specific proteins that were not found in whole tissue lysates (TL), including GAA, DYNLRB1, CLTB, SIRT3, CCT2, and muscle-specific HSPB2. We also observed structural anomalies, such as autophago-vacuole formation, irregularly shaped mitochondria, and glycogen deposition, which provide insights into the EL's contribution to AF and related pathways and molecular mechanisms. Overall, our findings suggest that EL play an important role in the development of AF over longer time frames, and provide a more detailed understanding of the underlying molecular processes involved.

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Section: Discussionmentioning

confidence: 99%

Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation

Ayagama

Charles

Bose

et al. 2023

Preprint

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“…The efficacy of NVS-PAK1-1 on solid cancers in preclinical models is yet to be conducted. A recent study by Genentech suggested that the toxicity of group-I PAK inhibitors may be associated with the inhibition of PAK2 [ 240 ], which is an advantage for NVS-PAK1-1 over all other known PAK inhibitors. Unfortunately, PAK2 is expressed and activated in most cancers, which creates questions about the suitability of NVS-PAK-1-1 as a cancer therapeutic.…”

Section: Inhibitors Of Paks and Their Potential Clinical Utilitymentioning

confidence: 99%

Targeting P21-Activated Kinase-1 for Metastatic Prostate Cancer

Somanath

Chernoff

Cummings

et al. 2023

Cancers

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Metastatic prostate cancer (mPCa) has limited therapeutic options and a high mortality rate. The p21-activated kinase (PAK) family of proteins is important in cell survival, proliferation, and motility in physiology, and pathologies such as infectious, inflammatory, vascular, and neurological diseases as well as cancers. Group-I PAKs (PAK1, PAK2, and PAK3) are involved in the regulation of actin dynamics and thus are integral for cell morphology, adhesion to the extracellular matrix, and cell motility. They also play prominent roles in cell survival and proliferation. These properties make group-I PAKs a potentially important target for cancer therapy. In contrast to normal prostate and prostatic epithelial cells, group-I PAKs are highly expressed in mPCA and PCa tissue. Importantly, the expression of group-I PAKs is proportional to the Gleason score of the patients. While several compounds have been identified that target group-I PAKs and these are active in cells and mice, and while some inhibitors have entered human trials, as of yet, none have been FDA-approved. Probable reasons for this lack of translation include issues related to selectivity, specificity, stability, and efficacy resulting in side effects and/or lack of efficacy. In the current review, we describe the pathophysiology and current treatment guidelines of PCa, present group-I PAKs as a potential druggable target to treat mPCa patients, and discuss the various ATP-competitive and allosteric inhibitors of PAKs. We also discuss the development and testing of a nanotechnology-based therapeutic formulation of group-I PAK inhibitors and its significant potential advantages as a novel, selective, stable, and efficacious mPCa therapeutic over other PCa therapeutics in the pipeline.

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“…However, the ubiquitin E3 ligase TRIM21 suppressed the p62-Keap1-Nrf2 antioxidant pathway in a doxorubicin-induced cardiac dysfunction model, and Trim21 knockout mice were protected from HF [ 96 ]. P21-activated kinase 2 (PAK2) targets Nrf2/Keap1 ubiquitination by mediating 3-hydroxy-3-methylglutaryl reductase degradation 1 (HRD1) expression, thereby alleviating detrimental ER stress and HF, offering another potential therapeutic strategy for HF [ 97 ]. Moreover, in a rat model of chronic HF, miR-129-5p was found to target Smad ubiquitin regulatory factor 1 (SMURF1) and repress the ubiquitination of PTEN to improve cardiac function [ 98 ].…”

Section: Interaction Of the Ups And Oxidative Stress In Cvdsmentioning

confidence: 99%

Intersection of the Ubiquitin–Proteasome System with Oxidative Stress in Cardiovascular Disease

Qiu

Chen²,

Li³

et al. 2022

IJMS

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Cardiovascular diseases (CVDs) present a major social problem worldwide due to their high incidence and mortality rate. Many pathophysiological mechanisms are involved in CVDs, and oxidative stress plays a vital mediating role in most of these mechanisms. The ubiquitin–proteasome system (UPS) is the main machinery responsible for degrading cytosolic proteins in the repair system, which interacts with the mechanisms regulating endoplasmic reticulum homeostasis. Recent evidence also points to the role of UPS dysfunction in the development of CVDs. The UPS has been associated with oxidative stress and regulates reduction–oxidation homeostasis. However, the mechanisms underlying UPS-mediated oxidative stress’s contribution to CVDs are unclear, especially the role of these interactions at different disease stages. This review highlights the recent research progress on the roles of the UPS and oxidative stress, individually and in combination, in CVDs, focusing on the pathophysiology of key CVDs, including atherosclerosis, ischemia–reperfusion injury, cardiomyopathy, and heart failure. This synthesis provides new insight for continued research on the UPS–oxidative stress interaction, in turn suggesting novel targets for the treatment and prevention of CVDs.

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Pak2 Regulation of Nrf2 Serves as a Novel Signaling Nexus Linking ER Stress Response and Oxidative Stress in the Heart

Cited by 20 publications

References 49 publications

Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation

Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation

Targeting P21-Activated Kinase-1 for Metastatic Prostate Cancer

Intersection of the Ubiquitin–Proteasome System with Oxidative Stress in Cardiovascular Disease

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