Cyclophilin A is a mitochondrial factor that forms complexes with p23. Correlative evidence for an antiapoptotic action

Daneri-Becerra, Cristina; Valeiras, Brenda; Gallo, Luciana I.; Lagadari, Mariana; Galigniana, Mario D.

doi:10.1242/jcs.253401

Cited by 11 publications

(7 citation statements)

References 69 publications

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“…Intracellular CyPA may play a role in the pathogenesis of cardiovascular diseases by acting as a chaperone and playing a role in protein folding, trafficking, and function [19]. However, recent findings show that a significant pool of CyPA is an intra-mitochondrial factor, enhancing antiapoptotic signals, and hence suggesting a role in cell survival [20]. Indeed, CyPA was found to inhibit oxidative stress and apoptosis by modulating the PI3K/Akt/mTOR signaling pathway [21] in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

Hernández

Tesoro

Ramírez-Carracedo

et al. 2021

IJMS

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In response to cardiac ischemia/reperfusion, proteolysis mediated by extracellular matrix metalloproteinase inducer (EMMPRIN) and its secreted ligand cyclophilin-A (CyPA) significantly contributes to cardiac injury and necrosis. Here, we aimed to investigate if, in addition to the effect on the funny current (I(f)), Ivabradine may also play a role against cardiac necrosis by reducing EMMPRIN/CyPA-mediated cardiac inflammation. In a porcine model of cardiac ischemia/reperfusion (IR), we found that administration of 0.3 mg/kg Ivabradine significantly improved cardiac function and reduced cardiac necrosis by day 7 after IR, detecting a significant increase in cardiac CyPA in the necrotic compared to the risk areas, which was inversely correlated with the levels of circulating CyPA detected in plasma samples from the same subjects. In testing whether Ivabradine may regulate the levels of CyPA, no changes in tissue CyPA were found in healthy pigs treated with 0.3 mg/kg Ivabradine, but interestingly, when analyzing the complex EMMPRIN/CyPA, rather high glycosylated EMMPRIN, which is required for EMMPRIN-mediated matrix metalloproteinase (MMP) activation and increased CyPA bonding to low-glycosylated forms of EMMPRIN were detected by day 7 after IR in pigs treated with Ivabradine. To study the mechanism by which Ivabradine may prevent secretion of CyPA, we first found that Ivabradine was time-dependent in inhibiting co-localization of CyPA with the granule exocytosis marker vesicle-associated membrane protein 1 (VAMP1). However, Ivabradine had no effect on mRNA expression nor in the proteasome and lysosome degradation of CyPA. In conclusion, our results point toward CyPA, its ligand EMMPRIN, and the complex CyPA/EMMPRIN as important targets of Ivabradine in cardiac protection against IR.

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Section: Discussionmentioning

confidence: 99%

Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

Hernández

Tesoro

Ramírez-Carracedo

et al. 2021

IJMS

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“…miR-378, another miRNA with the ability to enhance cell viability and inhibit cardiomyocyte apoptosis, was found to be down-regulated in the hearts of DOX-treated rats. The overexpression of miR-378 protected against DOX-induced energy imbalance and apoptosis, targeting lactate dehydrogenase A and cyclophilin A [134], a novel mitochondrial factor with antiapoptotic properties [159]. Unlike the miRs described above, miRs have also been shown to participate in the pathogenesis of DOX-induced cardiotoxicity and/or exacerbate injury.…”

Section: Micrornas (Mirs)mentioning

confidence: 99%

Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity

Leung

Poon

2022

IJMS

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Anthracyclines, such as doxorubicin, are effective chemotherapeutic agents for the treatment of cancer, but their clinical use is associated with severe and potentially life-threatening cardiotoxicity. Despite decades of research, treatment options remain limited. The mitochondria is commonly considered to be the main target of doxorubicin and mitochondrial dysfunction is the hallmark of doxorubicin-induced cardiotoxicity. Here, we review the pathogenic mechanisms of doxorubicin-induced cardiotoxicity and present an update on cardioprotective strategies for this disorder. Specifically, we focus on strategies that can protect the mitochondria and cover different therapeutic modalities encompassing small molecules, post-transcriptional regulators, and mitochondrial transfer. We also discuss the shortcomings of existing models of doxorubicin-induced cardiotoxicity and explore advances in the use of human pluripotent stem cell derived cardiomyocytes as a platform to facilitate the identification of novel treatments against this disorder.

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“…Cyclophilins are members of the immunophilin protein family, which is characterized by a signature domain containing PPIase activity 10 . They are ubiquitously expressed in prokaryotes and eukaryotes, ranging from bacteria, fungi, insects, plants and mammals 11 . Additionally, cyclophilins are widely expressed across many different organs 10 , 12 .…”

Section: A Brief Overview Of Cypa Structural Biologymentioning

confidence: 99%

“…The physiologic function of CyPA - PPIase isomerase activity has been documented as a molecular chaperone that regulates protein folding, trafficking and activities 11 , 20 , 21 . Several studies have also reported that CyPA is a multifunctional molecule with known major roles in cellular signaling, gene regulation, inflammation and apoptosis 21 - 23 .…”

Section: Physiologic and Pathophysiologic Roles Of Cypa In Generalmentioning

confidence: 99%

Current update on theranostic roles of cyclophilin A in kidney diseases

Hadpech¹,

Thongboonkerd²

2022

Theranostics

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Cyclophilin A (CyPA) or peptidylprolyl isomerase A (PPIA), an immunophilin with peptidyl-prolyl cis/trans isomerase (PPIase) activity, is an abundant cellular protein widely expressed across various cell types and tissues, including the kidney. Expression of CyPA in the kidney is relatively higher in proximal tubular epithelial cells than others along the nephron. Alterations in expression and secretion of CyPA play important roles in physiological processes and pathophysiology of several diseases affecting the kidney. Herein, we provide a brief overview of CyPA structural biology and present the current update on its theranostic roles in various kidney diseases, including diabetic nephropathy, acute kidney injury, chronic kidney disease, renal fibrosis, and nephrotoxicity associated with organ transplantation. Notably, the diagnostic/prognostic role for urinary CyPA in several of these kidney diseases is promising. Finally, future perspectives on the CyPA research, especially targeting CyPA for therapeutics, are discussed. A comprehensive understanding of the theranostic roles of CyPA in kidney diseases is expected to provide novel insights into the design of new therapeutic interventions and prevention strategies.

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Cyclophilin A is a mitochondrial factor that forms complexes with p23. Correlative evidence for an antiapoptotic action

Cited by 11 publications

References 69 publications

Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity

Current update on theranostic roles of cyclophilin A in kidney diseases

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