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Roles of Enos in Atherosclerosis Treatment

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Roles of Enos in Atherosclerosis Treatment Infammation Research (2019) 68:429–441 https://doi.org/10.1007/s00011-019-01229-9 Inflammation Research REVIEW Roles of eNOS in atherosclerosis treatment Fen‑fang Hong1 · Xiao‑yu Liang1 · Wei Liu1 · Sha Lv1 · Shu‑jin He1 · Hai‑bin Kuang1 · Shu‑long Yang1 Received: 10 July 2018 / Revised: 16 March 2019 / Accepted: 18 March 2019 / Published online: 1 April 2019 © Springer Nature Switzerland AG 2019 Abstract Background Atherosclerosis (AS) is the main pathogeny of coronary heart disease, cerebral infarction and peripheral vascular disease. Endothelial dysfunction is one of the important pathogenesis of AS. As an important endothelium-derived relaxa- tion factor, nitric oxide (NO) plays a role in cardiovascular protection and anti-AS function; but in the pathological state, endothelial nitric oxide synthase (eNOS) disorder causes an abnormal production of NO, which may damage endothelial function and trigger AS. This review summarized the research progresses in the treatment strategies for AS based on cor- recting the disordered eNOS/ NO signaling pathway. Main body According to the topic, select the search terms ‘atherosclerosis,’ ‘nitric oxide,’ ‘eNOS,’ ‘treatment,’ ‘manage- ment,’ ‘medication,’ ‘maintenance,’ ‘remission’. Using these terms, a structured literature search via multiple electronic databases was performed for the most recent trial evidence in recent years. We read and analyze these literatures carefully, classifed these literatures according to their content, and then summarized and outlined the common main points in these classifed literatures. Finally, literature data were organized to discuss these main points logically. We found that both aber- rant expression and dysfunction of eNOS are closely related to AS development, and some new treatment strategies aimed at eNOS have been proposed, including upregulation of eNOS expression and inhibition of eNOS uncoupling. The former one is mainly related to infammatory inhibition and protection of the PKB-eNOS signaling pathway; whereas the latter one is associated with the addition of the L-arginine substrate of eNOS, arginase inhibition, and the supplement of tetrahydro- biopterin, which can elevate no level. Conclusions eNOS can be an important target for prevention and treatment of AS, and eNOS drugs may be another potent class of efective therapeutic treatment for AS following traditional lipid-lowering, anti-platelet, vasodilator drugs. But apply- ing these experimental results to clinic treatment still requires further studies and development of biotechnology. Keywords Atherosclerosis · Endothelial nitric oxide synthase · Arginase · Tetrahydrobiopterin · Treatment Introduction all large and medium-sized arteries and causes a series of cardio and cerebrovascular diseases such as coronary heart Cardio- and cerebro-vascular diseases caused by athero- disease, cerebral infarction and renal vascular hypertension. sclerosis (AS) have been the number one cause of death Furthermore, AS-associated vascular diseases also serve as in the world for many years [1]. AS is involved in almost the main harmful results of diabetes mellitus [2]. Endothelial dysfunction plays important roles in AS pathogenesis. Nitric oxide (NO) derived from endothelial Responsible Editor: John Di Battista. cells can dilate blood vessels and inhibit platelet adhesion Fen-fang Hong, Xiao-yu Liang, Wei Liu, Sha Lv and Shu-jin He and aggregation. It also prevents the adhesion between leu- are co-frst authors. kocytes and endothelial cells, as well as restrains the pro- liferation of smooth muscle cells [3], suggesting its anti- * Hai-bin Kuang AS efects. NO is synthesized from arginine catalyzed by [email protected] nitric oxide synthase (NOS). There are three NOS subtypes, * Shu-long Yang including endothelial nitric oxide synthase (eNOS), induc- [email protected] ible nitric oxide synthase (iNOS), and neuronal nitric oxide 1 Department of Physiology, College of Medicine, Nanchang synthase (nNOS). University, Nanchang 330006, China Vol.:(0123456789)1 3 430 F. Hong et al. eNOS is a homodimer, and its C-terminal bonds nico- Therefore, correcting the disordered eNOS/NO pathway tinamide adenine dinucleotide phosphate(NADPH), favin for the treatment of AS and other related diseases is impor- mononucleotide (FMN), favin adenine dinucleotide (FAD) tant. Here, we reviewed the present treatment strategies for reductase and heme-binding region, whereas its amino ter- AS aimed at eNOS intervention after consulting a large minal bonds tetrahydrobiopterin4 (BH4), O2, the oxidase number of literatures. Our study procedure was shown in zone, and the medium calmodulin binding sequences of Fig. 1. L-arginine (L-Arg) [4]. Under physiological conditions, most of NO is produced from endothelial cells in which eNOS oxidates the guanidino nitrogen of L-Arg end. Endothelium- derived NO (eNO) is a multifunctional signaling molecule eNOS expression upregulation increases that, as an efective endogenous vasodilator, inhibits the key NO content to treat AS process in vascular lesion formation. eNO reduces the pro- duction of reactive oxygen species(ROS) and lipid peroxida- eNOS is one of three kinds of NOS. A number of studies tion [5]. In addition, eNO also has the efect of inhibiting [8, 9] have found that, with the development of AS lesions, platelet adhesion and aggregation, inhibiting adhesion mol- the expression level of eNOS decreased gradually. This ecule and chemokine expression, as well as reducing infam- fnding demonstrates that eNOS abnormality has an impor- matory cell infltration and smooth muscle cells (SMCs) tant infuence on AS. For example, the downregulation migration and proliferation [6]. eNO signaling pathways of eNOS expressions, the decreased eNOS activity and mainly include the phosphatidylinositol 3-kinase (PI3K)/ eNOS inhibitors all resulted in the decrease of NO syn- serine threonine protein kinase B (AKT)/eNOS pathway [7]. thesis, which can accelerate the development of AS dis- Thus, abnormal eNOS expression or its dysfunction ease. Therefore, treatments aimed at eNOS have become may cause NO production disorder, in turn damaging an important target for the treatment of AS. endothelial function [8]. That is a pathogenesis of AS. Fig. 1 Study procedure 1 3 431 Roles of eNOS in atherosclerosis treatment Upregulation of eNOS expression by regulating ciglitazone. Of interest, inhibiting AMPK abolished cigl- ox‑LDL itazone-mediated eNOS function, NO synthesis and angi- ogenesis, but increased RMVECs’ aging and apoptosis. Oxidized low-density lipoprotein (ox-LDL)-induced Further experiments showed that inhibition of peroxisome endothelial cell injury is thought to be the frst step in the proliferator-activated receptors (PPAR) signifcantly sup- pathogenesis of AS. Ox-LDL has high cytotoxicity, injuring pressed AMPK phosphorylation, eNOS expression and NO endothelial cell by reducing eNOS expression and increas- production [9]. ing iNOS expression to induce apoptosis of endothelial Bao et al. [11] found that ox-LDL signifcantly decreased cells, which accelerates the progression of AS (Fig. 2). Yin endothelial cell viability, increased lactate dehydroge- et al. found that epigallocatechin-3-gallate protects against nase (LDH) and IL-8 levels, inhibited NO production and ox-LDL-induced endothelial dysfunction through the Jag- induced cyclooxygenase-2 (COX-2) expression. Further- ged-1/Notch signaling pathway [10] (Table 1). In Xu et al. more, ox-LDL also stimulated the expression of hemag- study, the data showed that eNOS and Akt phosphorylation, glutinin-like oxidized low-density lipoprotein receptor-1 vascular endothelial growth factor (VEGF) expression and (LOX-1), ROS overproduction, p38 mitogen-activated pro- NO production were signifcantly decreased; moreover, the tein kinase (p38MAPK) phosphorylation, protein kinase B aging and apoptosis of rat microvascular endothelial cells (PKB) dephosphorylation and nuclear factorκB (NF-κB) (RMVECs) increased after ox-LDL induction for 24 h. All activation as well as inhibitor nuclear factor-kappa B (IκB) these changes were efectively reversed by ciglitazone pre- degradation. But, these ox-LDL-induced efects were sup- treatment. Meanwhile, the phosphorylation of adenosine pressed by puerarin pretreatment. These results suggest that 5′-monophosphate (AMP)-activated protein kinase (AMPK) puerarin inhibits ox-LDL-induced endothelial cell injuries was suppressed by ox-LDL, which was also prevented by via inhibition of the LOX-1-mediated p38MAPK-NF-κB Fig. 2 Regulating efects of oxidized low-density lipoprotein on endothelial dysfunction in atherosclerosis 1 3 432 Table 1 Mechanisms that treat atherosclerosis by the eNOS/NO pathway Pretreatment Animal Cell eNOS/NO levels Mechanism Relationship with atheroscle- References rosis Epigallocatechin-3-gallate HUVECs eNOS↑ ox-LDL-induced apoptosis↓, Inhibited the development of [6] (EGCG) iNOS↓ ox-LDL-diminished cell aortic atherosclerosis adhesion Ciglitazone Rat microvascular endothelial eNOS↑ Ciglitazone-mediated PPARγ Be efective in limiting athero- [7] cells (RMVECs) NO↑ activation suppresses LOX-1 sclerotic events and moderates the AMPK/ eNOS pathway Puerarin Endothelial cells eNOS↑ Inhibition of the LOX-1-me- Inhibits ox-LDL-induced [8] NO↑ diated p38MAPK-NF-κB endothelial cell injuries infammatory and the PKB– eNOS signaling pathways Coenzyme Q10 (CoQ10) HUVEC eNOS↑ Attenuated the ox-LDL- Provide new insight into the [10] iNOS↓ induced generation of possible molecular mecha- reactive oxygen species and nisms
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