Pin1 as Molecular Switch in Vascular Endothelium: Notes on Its Putative Role in Age-Associated Vascular Diseases.

Francesca Fagiani,Marieva Vlachou,Cristina Lanni,Marco Racchi,Stefano Govoni,Daniele Di Marino,Ilaria Canobbio,Alice Romagnoli

doi:10.3390/cells10123287

Francesca Fagiani, Marieva Vlachou + Show 6 more

Open Access

https://doi.org/10.3390/cells10123287

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Journal: Cells	Publication Date: Nov 24, 2021
Citations: 3	License type: CC BY 4.0

Affiliation: University of Pavia, Marche Polytechnic University

Abstract

By controlling the change of the backbones of several cellular substrates, the peptidyl-prolyl cis-trans isomerase Pin1 acts as key fine-tuner and amplifier of multiple signaling pathways, thereby inducing several biological consequences, both in physiological and pathological conditions. Data from the literature indicate a prominent role of Pin1 in the regulating of vascular homeostasis. In this review, we will critically dissect Pin1’s role as conformational switch regulating the homeostasis of vascular endothelium, by specifically modulating nitric oxide (NO) bioavailability. In this regard, Pin1 has been reported to directly control NO production by interacting with bovine endothelial nitric oxide synthase (eNOS) at Ser116-Pro117 (human equivalent is Ser114-Pro115) in a phosphorylation-dependent manner, regulating its catalytic activity, as well as by regulating other intracellular players, such as VEGF and TGF-β, thereby impinging upon NO release. Furthermore, since Pin1 has been found to act as a critical driver of vascular cell proliferation, apoptosis, and inflammation, with implication in many vascular diseases (e.g., diabetes, atherosclerosis, hypertension, and cardiac hypertrophy), evidence indicating that Pin1 may serve a pivotal role in vascular endothelium will be discussed. Understanding the role of Pin1 in vascular homeostasis is crucial in terms of finding a new possible therapeutic player and target in vascular pathologies, including those affecting the elderly (such as small and large vessel diseases and vascular dementia) or those promoting the full expression of neurodegenerative dementing diseases.

Highlights

The vascular endothelium, the active inner layer of the blood vessel, releases a wide array of biologically active molecules acting in an autocrine or paracrine fashion, thereby controlling arterial structure and vasodilatory, thrombolytic, and vaso-protective functions
Since Pin1 has been found to act as a critical driver of vascular cell proliferation, apoptosis, and inflammation, with implication in many vascular diseases, evidence indicating that Pin1 may serve a pivotal role in vascular endothelium will be discussed
Full-length human Pin1 cDNA was inserted in the endothelial nitric oxide synthase (eNOS) transfected cells and the results showed that Pin1 had an increased binding affinity for the S116D eNOS compared to wild-type bovine eNOS (WT eNOS), underscoring the importance of Ser116 phosphorylation on Pin1eNOS interaction [14]

Summary

Aging and the Vasculature

The vascular endothelium, the active inner layer of the blood vessel, releases a wide array of biologically active molecules acting in an autocrine or paracrine fashion, thereby controlling arterial structure and vasodilatory, thrombolytic, and vaso-protective functions. It regulates a number of biological functions, such as substrate exchange/transport, innate immunity, the regulation of vascular tone by balancing the production of vasodilators and vasoconstrictors, angiogenesis, and hemostasis by secreting antiplatelet and anticoagulant molecules (for a comprehensive review on the topic see [1]). The severity of endothelial dysfunction has been shown to have prognostic value for cardiovascular events [5]

The Role of the cis-trans Isomerase Pin1 in Vascular Endothelium

Indirect Regulation of NOS by Pin1

Conclusions