Pin1 in cardiovascular dysfunction: A potential double-edge role

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Abstract

Backgrounds

Our lab focused on the structural and functional properties of Pin1, which is the only known cistrans isomerase regulating pSer/pThr–Pro motifs in proteins and facilitates various signaling pathways. We are lucky enough to read the article, contributed by Costantino et al. in your esteemed journal, on the role of Pin1 in diabetes-induced vascular dysfunction. Pin1 regulates the production of nitric oxide (NO), which is a key physiological stimulator of blood vessels and promotes vascular relaxation responses significantly. However, the regulation of cardiovascular diseases by Pin1 is somewhat controversial.

Methods and results

We compared the recent studies that support the down-regulation, as well as up-regulation, of NO production by Pin1 and tried to explore the underlying molecular mechanisms. We especially compared the different regulations of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) by Pin1, which is potentially the major reason leading to the controversial role of Pin1. Interestingly, the regulation of both eNOS and iNOS by Pin1 involves a double-edge effect, positively and negatively, contributing to paradoxical Pin1 functions in different animal models and cell lines. The extremely complex Pin1-regulated signaling networks might further exacerbate distinct cellular responses in vivo and influence NO production.

Conclusions

Pin1 plays a dual role, both positive and negative, in regulating NO production and in mediating the pathogenesis of cardiovascular diseases. Pin1 functions may vary a lot under different circumstances. Future investigations should focus on eNOS as well as iNOS in order to increase authenticity and accuracy of results.

Introduction

Diabetes and its complications are serious diseases causing a heavy social burden, and cardiovascular disorder is a main risk of death in patients suffering from diabetes [1], [2], [3]. Hyperglycemia induces cardiovascular complications and hinders the treatment of cardiovascular diseases [4], [5]. Some key regulatory molecules have been discovered in the related studies until now, and emerging evidence gradually reveals that Pin1 plays an essential role in mediating the impact of diabetes on cardiovascular complications [6], [7], [8].

We are lucky enough to read the recent article contributed by Costantino et al. in your esteemed journal, which describes the regulation of diabetes-induced vascular dysfunction by Pin1 [8]. Costantino et al. demonstrated that high-concentration glucose attenuated the release of nitric oxide (NO) in human aortic endothelial cells (HAECs) contributing to vascular dysfunction, and juglone, a traditional inhibitor of Pin1, enhanced the production of NO and prevented glucose-induced impairment of NO bioactivity [8]. The result mainly indicates that Pin1 blocks the production of NO, however, some other studies evidence that the role of Pin1 in NO production and in cardiovascular diseases such as hypertension and atherosclerosis is somewhat controversial. Therefore, we wish to make a brief summary of the existing contradictory results and try to explain why these paradoxical phenomena occur.

Section snippets

Evidence to support down-regulation of eNOS and NO by Pin1

The impact of Pin1 on vascular function is mainly mediated by nitric oxide (NO), which promotes relaxation of blood vessels and guarantees normal physiological functions of blood vessels [9], [10], [11]. Impaired NO bioavailability potentially results in vascular dysfunction, cardiovascular diseases, and other complications [6], [8], [12], [13]. Costantino et al. concluded that Pin1 prevented NO bioavailability by inhibiting the activity of endothelial nitric oxide synthase (eNOS), which is an

Evidence to support up-regulation of eNOS and NO by Pin1

eNOS is inactivated when Ser116 is phosphorylated, and Chiasson et al. illustrated that Pin1 bound with Ser116-phosphorylated eNOS and promoted dephosphorylation of eNOS in rat aortic endothelial cells (RAECs) and mouse aortas consequently enhancing eNOS activity and NO production; Pin1 knockdown by RNAi or Pin1 inhibition by juglone prevented pSer116-dephosphorylation of eNOS via the vascular endothelial growth factor (VEGF)-dependent pathway, resulting in hyperphosphorylation of Ser116,

Potential mechanisms leading to the seemingly contradictory dual role of Pin1

These contradictions above may have plagued a lot of scientists in the related research fields. Therefore, it is extremely necessary to evaluate the reasons why Pin1 has the seemingly contradictory functions in the pathogenesis of vascular diseases that are correlated with metabolic dysfunction of NO. Several possible reasons are listed below for the reader's reference, and we briefly illustrated the potential underlying molecular mechanisms in Fig. 1.

Future orientations

The presented evidence primarily indicates that the double-edge regulation of eNOS and iNOS by Pin1 and the complicated signaling networks regulated by Pin1 may collectively result in varied NO production in different animal models and cell lines, providing some possible explanations for the controversial role of Pin1 in cardiovascular diseases such as hypertension caused by metabolic dysfunction of NO. This complex regulation of NO production by Pin1 would cause difficulties for the related

Finding source

Funding from Education Department of Hebei Province of China (no. QN20131051).

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

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