Arginase as a Critical Prooxidant Mediator in the Binomial Endothelial Dysfunction-Atherosclerosis

Arginase is a metalloenzyme which hydrolyzes L-arginine to L-ornithine and urea. Since its discovery, in the early 1900s, this enzyme has gained increasing attention, as literature reports have progressively pointed to its critical participation in regulating nitric oxide bioavailability. Indeed, accumulating evidence in the following years would picture arginase as a key player in vascular health. Recent studies have highlighted the arginase regulatory role in the progression of atherosclerosis, the latter an essentially prooxidant state. Apart from the fact that arginase has been proven to impair different metabolic pathways, and also as a consequence of this, the repercussions of the actions of such enzyme go further than first thought. In fact, such metalloenzyme exhibits direct implications in multiple cardiometabolic diseases, among which are hypertension, type 2 diabetes, and hypercholesterolemia. Considering the epidemiological repercussions of these clinical conditions, arginase is currently seen under the spotlights of the search for developing specific inhibitors, in order to mitigate its deleterious effects. That said, the present review focuses on the role of arginase in endothelial function and its participation in the establishment of atherosclerotic lesions, discussing the main regulatory mechanisms of the enzyme, also highlighting the potential development of pharmacological strategies in related cardiovascular diseases.

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Cystatin M/E (Cystatin 6): A Janus-Faced Cysteine Protease Inhibitor with Both Tumor-Suppressing and Tumor-Promoting Functions

Cancers ◽

10.3390/cancers13081877 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1877

Author(s):

Gilles Lalmanach ◽

Mariana Kasabova-Arjomand ◽

Fabien Lecaille ◽

Ahlame Saidi

Keyword(s):

Prognostic Significance ◽

Tight Binding ◽

Cysteine Protease Inhibitor ◽

Tumor Promoter ◽

Regulatory Mechanisms ◽

Placental Development ◽

Cysteine Cathepsins ◽

Cystatin M

Alongside its contribution in maintaining skin homeostasis and its probable involvement in fetal and placental development, cystatin M/E (also known as cystatin 6) was first described as a tumor suppressor of breast cancer. This review aims to provide an update on cystatin M/E with particular attention paid to its role during tumorigenesis. Cystatin M/E, which is related to type 2 cystatins, displays the unique property of being a dual tight-binding inhibitor of both legumain (also known as asparagine endopeptidase) and cysteine cathepsins L, V and B, while its expression level is epigenetically regulated via the methylation of the CST6 promoter region. The tumor-suppressing role of cystatin M/E was further reported in melanoma, cervical, brain, prostate, gastric and renal cancers, and cystatin M/E was proposed as a biomarker of prognostic significance. Contrariwise, cystatin M/E could have an antagonistic function, acting as a tumor promoter (e.g., oral, pancreatic cancer, thyroid and hepatocellular carcinoma). Taking into account these apparently divergent functions, there is an urgent need to decipher the molecular and cellular regulatory mechanisms of the expression and activity of cystatin M/E associated with the safeguarding homeostasis of the proteolytic balance as well as its imbalance in cancer.

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Infectious Agents Are Not Necessary for Murine Atherogenesis

Journal of Experimental Medicine ◽

10.1084/jem.191.8.1437 ◽

2000 ◽

Vol 191 (8) ◽

pp. 1437-1442 ◽

Cited By ~ 132

Author(s):

Samuel D. Wright ◽

Charlotte Burton ◽

Melba Hernandez ◽

Heide Hassing ◽

Judy Montenegro ◽

...

Keyword(s):

Chlamydia Pneumoniae ◽

Viral Infections ◽

Infectious Agent ◽

Infectious Agents ◽

Germ Free ◽

Atherosclerotic Lesions ◽

Apo E ◽

Microbial Agents ◽

Progression Of Atherosclerosis

Recent work has revealed correlations between bacterial or viral infections and atherosclerotic disease. One particular bacterium, Chlamydia pneumoniae, has been observed at high frequency in human atherosclerotic lesions, prompting the hypothesis that infectious agents may be necessary for the initiation or progression of atherosclerosis. To determine if responses to gram-negative bacteria are necessary for atherogenesis, we first bred atherosclerosis-prone apolipoprotein (apo) E−/− (deficient) mice with animals incapable of responding to bacterial lipopolysaccharide. Atherogenesis was unaffected in doubly deficient animals. We further tested the role of infectious agents by creating a colony of germ-free apo E−/− mice. These animals are free of all microbial agents (bacterial, viral, and fungal). Atherosclerosis in germ-free animals was not measurably different from that in animals raised with ambient levels of microbial challenge. These studies show that infection is not necessary for murine atherosclerosis and that, unlike peptic ulcer, Koch's postulates cannot be fulfilled for any infectious agent in atherosclerosis.

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Metabolic and Metabo-Clinical Signatures of T2D, Obesity, Retinopathy and Dyslipidemia.

10.2337/figshare.16896382.v1 ◽

2021 ◽

Author(s):

Noha A. Yousri ◽

Karsten Suhre ◽

Esraa Yassin ◽

Alya Al-Shakaki ◽

Amal Robay ◽

...

Keyword(s):

Metabolic Pathways ◽

Microvascular Complications ◽

Glutathione Metabolism ◽

High Cholesterol ◽

Clinical Variables ◽

Cholesterol Levels ◽

Very High ◽

Independent Cohort

Macro- and microvascular complications of type 2 diabetes (T2D), obesity, and dyslipidemia share common metabolic pathways. Here, using a total of 1,300 metabolites from 996 Qatari adults (57% with T2D) and 1,159 metabolites from an independent cohort of 2,618 individuals from the Qatar BioBank (11% with T2D), we identified 373 metabolites associated with T2D, obesity, retinopathy, dyslipidemia and lipoprotein levels, 161 of which were novel. Novel metabolites included phospholipids, sphingolipids, lysolipids, fatty acids, dipeptides, and metabolites of the urea cycle and xanthine, steroid and glutathione metabolism. The identified metabolites enrich pathways of oxidative stress, lipotoxicity, glucotoxicity and proteolysis. Second, we identified 15 patterns we defined as “metabo-clinical signatures.” These are clusters of T2D patients that group together based on metabolite levels and reveal the same clustering in two or more clinical variables (obesity, LDL, HDL, triglycerides, retinopathy). These signatures revealed metabolic pathways associated with different clinical patterns and identified patients with extreme (very high/low) clinical variables associated with extreme metabolite levels in specific pathways. Among our novel findings are the role of N-acetylmethionine in retinopathy in conjunction with dyslipidemia and the possible roles of N-acetylvaline and pyroglutamine in association with high cholesterol levels and kidney function.

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Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9270107 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Shengjie Yang ◽

Min Wu ◽

Xiaoya Li ◽

Ran Zhao ◽

Yixi Zhao ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein ◽

Atherosclerotic Lesions ◽

Different Types ◽

The Unfolded Protein Response ◽

Protein Response ◽

Er Homeostasis ◽

Progression Of Atherosclerosis

Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis and related cardiovascular diseases (CVDs). It occurs due to various pathological factors that interfere with ER homeostasis, resulting in the accumulation of unfolded or misfolded proteins in the ER lumen, thereby causing ER dysfunction. Here, we discuss the role of ER stress in different types of cells in atherosclerotic lesions. This discussion includes the activation of apoptotic and inflammatory pathways induced by prolonged ER stress, especially in advanced lesional macrophages and endothelial cells (ECs), as well as common atherosclerosis-related ER stressors in different lesional cells, which all contribute to the clinical progression of atherosclerosis. In view of the important role of ER stress and the unfolded protein response (UPR) signaling pathways in atherosclerosis and CVDs, targeting these processes to reduce ER stress may be a novel therapeutic strategy.

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Novel approach to pathophysiology of type 2 diabetes mellitus

Diabetes Mellitus ◽

10.14341/dm2013449-51 ◽

2013 ◽

Vol 16 (4) ◽

pp. 49-51

Author(s):

Emil' Kopeevich Mukhamedzhanov ◽

Oleg Viktorovich Esyrev

Keyword(s):

Diabetes Mellitus ◽

Protein Metabolism ◽

Metabolic Pathways ◽

Energy Homeostasis ◽

Insulin Signalling ◽

Carbon Chain ◽

Novel Approach ◽

Key Factor

In this paper, we present a model of interplay between protein, lipid and carbohydrate metabolic pathways with regard to the carbon chain transporting systems, as well as generation and consumption of energy. This model elucidates the role of protein metabolism in the impairment of glucose tolerance during the absorption period. We also discuss the effects on energy homeostasis exercised by cytokines via mTOR pathway (the key factor of insulin signalling) considering the phenomenon of insulin resistance.

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Diabetic atherosclerosis: is there a role for the hypoxia-inducible factors?

Bioscience Reports ◽

10.1042/bsr20200026 ◽

2020 ◽

Vol 40 (8) ◽

Author(s):

Daniela Pirri ◽

Maria Fragiadaki ◽

Paul C. Evans

Keyword(s):

Metabolic Syndrome ◽

Vascular Inflammation ◽

Hypoxia Inducible Factor ◽

Transcription Factor Family ◽

Juvenile Form ◽

Multiple Risk Factors ◽

The Metabolic Syndrome ◽

Progression Of Atherosclerosis

Abstract Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors, including diabetes. Diabetes is associated with either an insulin deficiency in its juvenile form or with insulin resistance and obesity in Type 2 diabetes mellitus, and the latter is clustered with other comorbidities to define the metabolic syndrome. Diabetes and metabolic syndrome are complex pathologies and are associated with cardiovascular risk via vascular inflammation and other mechanisms. Several transcription factors are activated upon diabetes-driven endothelial dysfunction and drive the progression of atherosclerosis. In particular, the hypoxia-inducible factor (HIF) transcription factor family is a master regulator of endothelial biology and is raising interest in the field of atherosclerosis. In this review, we will present an overview of studies contributing to the understanding of diabetes-driven atherosclerosis, integrating the role of HIF in this disease with the knowledge of its functions in metabolic syndrome and diabetic scenario.

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Metabolic and Metabo-Clinical Signatures of T2D, Obesity, Retinopathy and Dyslipidemia.

10.2337/figshare.16896382 ◽

2021 ◽

Author(s):

Noha A. Yousri ◽

Karsten Suhre ◽

Esraa Yassin ◽

Alya Al-Shakaki ◽

Amal Robay ◽

...

Keyword(s):

Metabolic Pathways ◽

Microvascular Complications ◽

Glutathione Metabolism ◽

High Cholesterol ◽

Clinical Variables ◽

Cholesterol Levels ◽

Very High ◽

Independent Cohort

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FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells

AJP Cell Physiology ◽

10.1152/ajpcell.00106.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. C538-C546 ◽

Cited By ~ 104

Author(s):

Yong-Xiao Wang ◽

Yun-Min Zheng ◽

Qi-Bing Mei ◽

Qinq-Song Wang ◽

Mei Lin Collier ◽

...

Keyword(s):

Smooth Muscle ◽

Ryanodine Receptors ◽

Regulatory Mechanisms ◽

Contraction Coupling ◽

Fk506 Binding Protein ◽

Cyclic Adp Ribose ◽

Intracellular Ca ◽

Relationship Of

Intracellular Ca2+ release through ryanodine receptors (RyRs) plays important roles in smooth muscle excitation-contraction coupling, but the underlying regulatory mechanisms are poorly understood. Here we show that FK506 binding protein of 12.6 kDa (FKBP12.6) associates with and regulates type 2 RyRs (RyR2) in tracheal smooth muscle. FKBP12.6 binds to RyR2 but not other RyR or inositol 1,4,5-trisphosphate receptors, and FKBP12, known to bind to and modulate skeletal RyRs, does not associate with RyR2. When dialyzed into tracheal myocytes, cyclic ADP-ribose (cADPR) alters spontaneous Ca2+ release at lower concentrations and produces macroscopic Ca2+ release at higher concentrations; neurotransmitter-evoked Ca2+ release is also augmented by cADPR. These actions are mediated through FKBP12.6 because they are inhibited by molar excess of recombinant FKBP12.6 and are not observed in myocytes from FKBP12.6-knockout mice. We also report that force development in FKBP12.6-null mice, observed as a decrease in the concentration/tension relationship of isolated trachealis segments, is impaired. Taken together, these findings point to an important role of the FKBP12.6/RyR2 complex in stochastic (spontaneous) and receptor-mediated Ca2+ release in smooth muscle.

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