Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes

Paneni, Francesco; Costantino, Sarah; Castello, Lorenzo; Battista, Rodolfo; Capretti, G; Chiandotto, Sergio; D’Amario, Domenico; Scavone, Giuseppe; Villano, Angelo; Rustighi, Alessandra; Crea, Filippo; Pitocco, Dario; Lanza, Gaetano Antonio; Volpe, Massimo; Sal, Giannino De; Lüscher, Thomas F.; Cosentino, Francesco

doi:10.1093/eurheartj/ehu179

Cited by 82 publications

(75 citation statements)

References 39 publications

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“…Using Pin1 -/ -transgenic mice, the authors confirmed the involvement of this enzyme in the hyperglycemia-induced mitochondrial superoxide overproduction. Finally, an increased Pin1 expression and activity was also found in the blood of type II diabetic patients and correlates with HbA1c and fasting plasma glucose concentrations (67). Pin1 activity also correlates with the concentration of 8-iso-prostaglandin F2a, a marker of oxidative stress.…”

Section: Glucose Metabolism and Ros Generationmentioning

confidence: 82%

“…Regarding the potential pathways involved in hyperglycemia-induced ROS generation, an elegant study recently described the increased expression and activity of the peptidyl-prolyl cis-trans isomerase (Pin1) and of the Ser-36 phosphorylation by the growth factor adapter protein (p66Shc), associated with an increased mitochondrial superoxide concentration in human aortic endothelial cells exposed to high glucose concentrations (67) (Fig. 4).…”

Section: Glucose Metabolism and Ros Generationmentioning

confidence: 99%

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Metabolic Alterations Induce Oxidative Stress in Diabetic and Failing Hearts: Different Pathways, Same Outcome

Roul

Recchia

2015

Antioxidants & Redox Signaling

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Significance: Several authors have proposed a link between altered cardiac energy substrate metabolism and reactive oxygen species (ROS) generation. A cogent evidence of this association has been found in diabetic cardiomyopathy (dCM); however, experimental findings in animal models of heart failure (HF) and in human myocardium also seem to support the coexistence of the two alterations in HF. Critical Issues: Two important questions remain open: whether pathological changes in metabolism play an important role in enhancing oxidative stress and whether there is a common pathway linking altered substrate utilization and activation of ROSgenerating enzymes, independently of the underlying cardiac pathology. In this regard, the comparison between dCM and HF is intriguing, in that these pathological conditions display very different cardiac metabolic phenotypes. Recent Advances: Our literature review on this topic indicates that a vast body of knowledge is now available documenting the relationship between the metabolism of energy substrates and ROS generation in dCM. In some cases, biochemical mechanisms have been identified. On the other hand, only a few and relatively recent studies have explored this phenomenon in HF and their conclusions are not consistent. Future Directions: Better methods of investigation, especially in vivo, will be necessary to test whether the metabolic fate of certain substrates is causally linked to ROS production. If successful, these studies will place a new emphasis on the potential clinical relevance of metabolic modulators, which might indirectly mitigate cardiac oxidative stress in dCM, HF, and, possibly, in other pathological conditions. Antioxid. Redox Signal. 22, 1502Signal. 22, -1514

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Section: Glucose Metabolism and Ros Generationmentioning

confidence: 82%

Section: Glucose Metabolism and Ros Generationmentioning

confidence: 99%

Metabolic Alterations Induce Oxidative Stress in Diabetic and Failing Hearts: Different Pathways, Same Outcome

Roul

Recchia

2015

Antioxidants & Redox Signaling

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“…Initial studies indicated that Pin1 suppresses basal eNOS activity in a manner analogous to the tonic suppression of eNOS activity by its association with caveolin-1 [83], a mechanism that may be of particular relevance in endothelial cells exposed to high glucose concentrations. Certainly, pharmacological inhibition or genetic deletion of Pin1 in diabetic mice was shown to be protective against mitochondrial oxidative stress, endothelial dysfunction and vascular inflammation [84,85]. Others have reported that the association of eNOS with Pin1 enables the dephosphorylation of Ser116 and stimulates NO production and demonstrated that a pharmacological inhibitor of Pin1 increased aortic eNOS Ser116 phosphorylation, endothelial dysfunction and hypertension, findings that were reproduced using Pin1-deficient mice [86].…”

Section: Interactions Indirectly Affecting Enos Functionmentioning

confidence: 98%

The eNOS signalosome and its link to endothelial dysfunction

Siragusa

Fleming

2016

Pflugers Arch - Eur J Physiol

140

111

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Endothelial nitric oxide synthase (eNOS) plays an essential role in the regulation of endothelial function and acts as a master regulator of vascular tone and homeostasis through the generation of the gasotransmitter nitric oxide (NO). The complex network of events mediating efficient NO synthesis is regulated by post-translational modifications and protein-protein interactions. Dysregulation of these mechanisms induces endothelial dysfunction, a term often used to refer to reduced NO bioavailability and consequent alterations in endothelial function, that are a hallmark of many cardiovascular diseases. Endothelial dysfunction is linked to eNOS uncoupling, which consists of a switch from the generation of NO to the generation of superoxide anions and hydrogen peroxide. This review provides an overview of the eNOS signalosome, integrating past and recently described protein-protein interactions that have been shown to play a role in the modulation of eNOS activity with implications for cardiovascular pathophysiology. The mechanisms underlying eNOS uncoupling and clinically relevant strategies that were adopted to influence them are also discussed.

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“…Highly increased Pin1 levels induce the onset of obesity, the nonalcoholic fatty liver disease, diabetes mellitus and atherosclerosis (Nakatsu et al, 2011(Nakatsu et al, , 2012Lu et al, 2013;Paneni et al, 2015). Additionally, Pin1 has a biphasic effect on the insulin receptor substrate pathway (Saltiel and Kahn, 2001).…”

Section: Pin1 Is Involved In the Metabolic Syndromementioning

confidence: 99%

Structure and function of the human parvulins Pin1 and Par14/17

Matena

Rehic

Hönig

et al. 2018

Biological Chemistry

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Parvulins belong to the family of peptidyl-prolyl cis/trans isomerases (PPIases) assisting in protein folding and in regulating the function of a broad variety of proteins in all branches of life. The human representatives Pin1 and Par14/17 are directly involved in processes influencing cellular maintenance and cell fate decisions such as cell-cycle progression, metabolic pathways and ribosome biogenesis. This review on human parvulins summarizes the current knowledge of these enzymes and intends to oppose the well-studied Pin1 to its less wellexamined homolog human Par14/17 with respect to structure, catalytic and cellular function.

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Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes

Abstract: Pin1 drives diabetic vascular disease by causing mitochondrial oxidative stress, eNOS dysregulation as well as NF-kB-induced inflammation. These findings provide molecular insights for novel mechanism-based therapeutic strategies in patients with diabetes.

Cited by 82 publications

References 39 publications

Metabolic Alterations Induce Oxidative Stress in Diabetic and Failing Hearts: Different Pathways, Same Outcome

Metabolic Alterations Induce Oxidative Stress in Diabetic and Failing Hearts: Different Pathways, Same Outcome

The eNOS signalosome and its link to endothelial dysfunction

Structure and function of the human parvulins Pin1 and Par14/17

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