Pin1 in cardiovascular dysfunction: A potential double-edge role
Graphical abstract
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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Cited by (13)
A preliminary identification of PIN1 SNP linkage in patients with coronary heart disease from Handan, China
2021, Revista Portuguesa de CardiologiaCitation Excerpt :rs2233678 is considered an important SNP that affects PIN1 transcription and Pin1 protein levels,10,17 whereas only the WT G allele was identified in our study population, implying that the GG genotype might be a risk factor for CHD, which necessitates further investigations in large-scale case-control studies in the future. Typical CHD therapies such as nitrate esters, calcium channel blockers and estrogens show beneficial therapeutic efficacy by improving NO-stimulated vascular diastolic function, but recent evidence supports the hypothesis that higher Pin1 may reduce NO production and result in coronary atherosclerosis.7,8,12,13 Therefore, a possible association of the polymorphic patterns of the PIN1 gene and CHD should be considered.
The association of rs2233679 in the PIN1 gene promoter with the risk of Coronary Artery Disease in Chinese female individuals
2020, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :The deposition of cholesterol, lipids, wastes and platelets can result in arterial plaques and coronary atherosclerosis, and then narrow coronary arteries cannot supply enough blood and oxygen to the heart gradually leading to CAD, one of the leading causes of death worldwide.13–16 The formation of coronary plaques is accelerated by attenuated diastolic movement of coronary arteries, but the small signaling molecule nitric oxide (NO), mainly produced by the endothelial nitric oxide synthase (eNOS), promotes vascular vasodilation function and prevents waste deposition in coronary arteries.17–19 Anti-CAD drugs such as nitrate esters, calcium antagonists and estrogens perform a variety of functions including up-regulating NO bioactivity.
Promising hen egg-derived proteins/peptides (EDPs) for food engineering, natural products and precision medicines
2020, Research in Veterinary ScienceA post-surgical adjunctive hypoxic therapy for myocardial infarction: Initiate endogenous cardiomyocyte proliferation in adults
2019, Medical HypothesesCitation Excerpt :As we know, blood lipids, cholesterol, platelet aggregation, radiation, smoking and drinking are some risk factors that may lead to MI [1–3]. Recently, a lot of recent studies developed prophylactic drugs [3], immunological and microRNA biomarkers [1,4], vasoactive medicines [5], gene therapy [6], carbon monoxide-releasing molecules [7], nitric oxide regulators and Pin1 inhibitors [8–10], etc., putting forward the mechanisms, prevention and treatment of MI. However, MI still represents the major cause of cardiovascular morbidity and mortality, despite all our efforts to develop novel medicines and interventional procedures [11–14].
A novel glucose-Pin1-eNOS-NO signaling axis links diabetes mellitus with cardiovascular diseases
2018, International Journal of CardiologyRole of oxidative stress in the process of vascular remodeling following coronary revascularization
2018, International Journal of CardiologyCitation Excerpt :Notably, a controversial role of Pin1 in the regulation of NO and in mediating the pathogenesis of cardiovascular diseases has been recently underscored, as a likely consequence of both eNOS and iNOS regulation. The latter phenomenon involves a double-edge effect, positively and negatively, contributing to paradoxical Pin1 functions in different animal models and cell lines [82]. Hydrogen sulfide (H2S) is a gas produced endogenously by cystathionine γ-lyase, cystathionine β-synthase and 3 mercaptopyruvate sulfurtransferase [83].