Inhibition of Gastrin-Releasing Peptide Attenuates Phosphate-Induced Vascular Calcification

Vascular calcification is the pathological deposition of calcium/phosphate in the vascular system and is closely associated with cardiovascular morbidity and mortality. Here, we investigated the role of gastrin-releasing peptide (GRP) in phosphate-induced vascular calcification and its potential regulatory mechanism. We found that the silencing of GRP gene and treatment with the GRP receptor antagonist, RC-3095, attenuated the inorganic phosphate-induced calcification of vascular smooth muscle cells (VSMCs). This attenuation was caused by inhibiting phenotype change, apoptosis and matrix vesicle release in VSMCs. Moreover, the treatment with RC-3095 effectively ameliorated phosphate-induced calcium deposition in rat aortas ex vivo and aortas of chronic kidney disease in mice in vivo. Therefore, the regulation of the GRP-GRP receptor axis may be a potential strategy for treatment of diseases associated with excessive vascular calcification.

Download Full-text

The Dual Role of Vitamin K2 in “Bone-Vascular Crosstalk”: Opposite Effects on Bone Loss and Vascular Calcification

Nutrients ◽

10.3390/nu13041222 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1222

Author(s):

Domitilla Mandatori ◽

Letizia Pelusi ◽

Valeria Schiavone ◽

Caterina Pipino ◽

Natalia Di Pietro ◽

...

Keyword(s):

Bone Loss ◽

Vascular Calcification ◽

Vascular System ◽

The Elderly ◽

Food Supplement ◽

Vitamin K2 ◽

Bioactive Molecules ◽

Calcium Deposition ◽

Age Related

Osteoporosis (OP) and vascular calcification (VC) represent relevant health problems that frequently coexist in the elderly population. Traditionally, they have been considered independent processes, and mainly age-related. However, an increasing number of studies have reported their possible direct correlation, commonly defined as “bone-vascular crosstalk”. Vitamin K2 (VitK2), a family of several natural isoforms also known as menaquinones (MK), has recently received particular attention for its role in maintaining calcium homeostasis. In particular, VitK2 deficiency seems to be responsible of the so-called “calcium paradox” phenomenon, characterized by low calcium deposition in the bone and its accumulation in the vessel wall. Since these events may have important clinical consequences, and the role of VitK2 in bone-vascular crosstalk has only partially been explained, this review focuses on its effects on the bone and vascular system by providing a more recent literature update. Overall, the findings reported here propose the VitK2 family as natural bioactive molecules that could be able to play an important role in the prevention of bone loss and vascular calcification, thus encouraging further in-depth studies to achieve its use as a dietary food supplement.

Download Full-text

Acid sphingomyelinase promotes SGK1-dependent vascular calcification

Clinical Science ◽

10.1042/cs20201122 ◽

2021 ◽

Vol 135 (3) ◽

pp. 515-534

Author(s):

Trang Thi Doan Luong ◽

Rashad Tuffaha ◽

Mirjam Schuchardt ◽

Barbara Moser ◽

Nadeshda Schelski ◽

...

Keyword(s):

Vascular Calcification ◽

Ex Vivo ◽

Acid Sphingomyelinase ◽

Upstream Regulator ◽

Key Factor ◽

Complex Signaling ◽

High Phosphate

Abstract In chronic kidney disease (CKD), hyperphosphatemia is a key factor promoting medial vascular calcification, a common complication associated with cardiovascular events and high mortality. Vascular calcification involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs), but the complex signaling events inducing pro-calcific pathways are incompletely understood. The present study investigated the role of acid sphingomyelinase (ASM)/ceramide as regulator of VSMC calcification. In vitro, both, bacterial sphingomyelinase and phosphate increased ceramide levels in VSMCs. Bacterial sphingomyelinase as well as ceramide supplementation stimulated osteo-/chondrogenic transdifferentiation during control and high phosphate conditions and augmented phosphate-induced calcification of VSMCs. Silencing of serum- and glucocorticoid-inducible kinase 1 (SGK1) blunted the pro-calcific effects of bacterial sphingomyelinase or ceramide. Asm deficiency blunted vascular calcification in a cholecalciferol-overload mouse model and ex vivo isolated-perfused arteries. In addition, Asm deficiency suppressed phosphate-induced osteo-/chondrogenic signaling and calcification of cultured VSMCs. Treatment with the functional ASM inhibitors amitriptyline or fendiline strongly blunted pro-calcific signaling pathways in vitro and in vivo. In conclusion, ASM/ceramide is a critical upstream regulator of vascular calcification, at least partly, through SGK1-dependent signaling. Thus, ASM inhibition by repurposing functional ASM inhibitors to reduce the progression of vascular calcification during CKD warrants further study.

Download Full-text

Research Models for Studying Vascular Calcification

International Journal of Molecular Sciences ◽

10.3390/ijms21062204 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2204 ◽

Cited By ~ 2

Author(s):

Jaqueline Herrmann ◽

Milen Babic ◽

Markus Tölle ◽

Markus van der Giet ◽

Mirjam Schuchardt

Keyword(s):

Animal Models ◽

Vascular Calcification ◽

Ex Vivo ◽

Systemic Disease ◽

Treatment Options ◽

Aortic Tissue ◽

Cardiovascular Morbidity And Mortality ◽

Culture Models

Calcification of the vessel wall contributes to high cardiovascular morbidity and mortality. Vascular calcification (VC) is a systemic disease with multifaceted contributing and inhibiting factors in an actively regulated process. The exact underlying mechanisms are not fully elucidated and reliable treatment options are lacking. Due to the complex pathophysiology, various research models exist evaluating different aspects of VC. This review aims to give an overview of the cell and animal models used so far to study the molecular processes of VC. Here, in vitro cell culture models of different origins, ex vivo settings using aortic tissue and various in vivo disease-induced animal models are summarized. They reflect different aspects and depict the (patho)physiologic mechanisms within the VC process.

Download Full-text

Uremic Toxins and Vascular Calcification–Missing the Forest for All the Trees

Toxins ◽

10.3390/toxins12100624 ◽

2020 ◽

Vol 12 (10) ◽

pp. 624 ◽

Cited By ~ 1

Author(s):

Nikolas Rapp ◽

Pieter Evenepoel ◽

Peter Stenvinkel ◽

Leon Schurgers

Keyword(s):

Vascular Calcification ◽

Vascular System ◽

State Of The Art ◽

Cardiorenal Syndrome ◽

Uremic Toxins ◽

Biological Mechanisms ◽

Cardiovascular Morbidity And Mortality ◽

Experimental Protocols ◽

Reduced Kidney Function

The cardiorenal syndrome relates to the detrimental interplay between the vascular system and the kidney. The uremic milieu induced by reduced kidney function alters the phenotype of vascular smooth muscle cells (VSMC) and promotes vascular calcification, a condition which is strongly linked to cardiovascular morbidity and mortality. Biological mechanisms involved include generation of reactive oxygen species, inflammation and accelerated senescence. A better understanding of the vasotoxic effects of uremic retention molecules may reveal novel avenues to reduce vascular calcification in CKD. The present review aims to present a state of the art on the role of uremic toxins in pathogenesis of vascular calcification. Evidence, so far, is fragmentary and limited with only a few uremic toxins being investigated, often by a single group of investigators. Experimental heterogeneity furthermore hampers comparison. There is a clear need for a concerted action harmonizing and standardizing experimental protocols and combining efforts of basic and clinical researchers to solve the complex puzzle of uremic vascular calcification.

Download Full-text

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000116 ◽

2012 ◽

Vol 82 (3) ◽

pp. 228-232 ◽

Cited By ~ 7

Author(s):

Mauro Serafini ◽

Giuseppa Morabito

Keyword(s):

Antioxidant Capacity ◽

Dietary Intervention ◽

Ex Vivo ◽

The Body ◽

Dietary Polyphenols ◽

Enzymatic Antioxidant ◽

Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Download Full-text

Cardiovascular disease and osteoporosis: is there a link between lipids and bone?

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1258/0004563021902134 ◽

2002 ◽

Vol 39 (3) ◽

pp. 203-210 ◽

Cited By ~ 37

Author(s):

John R Burnett ◽

Samuel D Vasikaran

Keyword(s):

Cardiovascular Disease ◽

Bone Density ◽

Vascular Calcification ◽

Cholesterol Biosynthesis ◽

Hormone Replacement ◽

Plasma Lipid ◽

Clinical Effects ◽

Cardiovascular Morbidity And Mortality ◽

The Relationship

Atherosclerotic heart disease and osteoporosis are both diseases of old age. Evidence is accumulating for a link between vascular and bone disease. Calcification is a common feature of atherosclerotic plaques, and osteoporosis is associated with both atherosclerosis and vascular calcification. However, the relationship of vascular calcification to the pathogenesis of atherosclerosis remains incompletely understood. Hormone replacement therapy has beneficial effects in the prevention of both atherosclerosis and osteoporosis. Bisphosphonates inhibit bone resorption and are used in the treatment of osteoporosis, whereas the statins inhibit cholesterol biosynthesis and are used for the treatment of atherosclerosis. We have reviewed recent advances in the knowledge of the actions of bisphosphonates and statins at the cellular, molecular and end-organ levels in order to examine the relationship between cardiovascular disease and osteoporosis and to explore the link between lipids and bones. These studies suggest that the mechanism of actions of these two classes of drugs at the cellular level may not be mutually exclusive. There are some early clinical data to complement these findings, suggesting that statins increase bone density and bisphosphonates may have a beneficial effect in vivo on plasma lipid levels and on the atherosclerotic process. Properly designed prospective studies that examine the effect of statins on bone density and fractures, as well as the effects of bisphosphonates on lipid profiles, atherosclerotic progression and cardiovascular morbidity and mortality are needed to define clearly the clinical effects and potential new roles for these agents.

Download Full-text

Oxidized LDLs as Signaling Molecules

Antioxidants ◽

10.3390/antiox10081184 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1184

Author(s):

Jean-Marc Zingg ◽

Adelina Vlad ◽

Roberta Ricciarelli

Keyword(s):

Free Radicals ◽

Cellular Response ◽

Vascular System ◽

Signaling Molecules ◽

Scavenger Receptors ◽

Physiological Relevance ◽

Reactive Radicals ◽

Accumulation Of Lipids

Levels of oxidized low-density lipoproteins (oxLDLs) are usually low in vivo but can increase whenever the balance between formation and scavenging of free radicals is impaired. Under normal conditions, uptake and degradation represent the physiological cellular response to oxLDL exposure. The uptake of oxLDLs is mediated by cell surface scavenger receptors that may also act as signaling molecules. Under conditions of atherosclerosis, monocytes/macrophages and vascular smooth muscle cells highly exposed to oxLDLs tend to convert to foam cells due to the intracellular accumulation of lipids. Moreover, the atherogenic process is accelerated by the increased expression of the scavenger receptors CD36, SR-BI, LOX-1, and SRA in response to high levels of oxLDL and oxidized lipids. In some respects, the effects of oxLDLs, involving cell proliferation, inflammation, apoptosis, adhesion, migration, senescence, and gene expression, can be seen as an adaptive response to the rise of free radicals in the vascular system. Unlike highly reactive radicals, circulating oxLDLs may signal to cells at more distant sites and possibly trigger a systemic antioxidant defense, thus elevating the role of oxLDLs to that of signaling molecules with physiological relevance.

Download Full-text

The Role of In Vivo and Ex Vivo Diagnostic Tools in Severe Delayed Immune-Mediated Adverse Antibiotic Drug Reactions

The Journal of Allergy and Clinical Immunology In Practice ◽

10.1016/j.jaip.2020.12.052 ◽

2021 ◽

Author(s):

Ana Copaescu ◽

Effie Mouhtouris ◽

Sara Vogrin ◽

Fiona James ◽

Kyra Y.L. Chua ◽

...

Keyword(s):

Ex Vivo ◽

Diagnostic Tools ◽

Drug Reactions ◽

Immune Mediated ◽

Antibiotic Drug

Download Full-text

Heparan sulfate and heparin interactions with proteins

Journal of The Royal Society Interface ◽

10.1098/rsif.2015.0589 ◽

2015 ◽

Vol 12 (110) ◽

pp. 20150589 ◽

Cited By ~ 108

Author(s):

Maria C. Z. Meneghetti ◽

Ashley J. Hughes ◽

Timothy R. Rudd ◽

Helena B. Nader ◽

Andrew K. Powell ◽

...

Keyword(s):

Heparan Sulfate ◽

Ex Vivo ◽

Sequence Specificity ◽

Structure Activity ◽

Multiple Binding Sites ◽

Multiple Binding ◽

Heparin Activity

Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissue-specific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro , ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. The properties that have been thought to bestow protein binding and biological activity upon HS and heparin vary from high levels of sequence specificity to a dependence on charge. In contrast to these opposing opinions, we will argue that the evidence supports both a level of redundancy and a degree of selectivity in the structure–activity relationship. The relationship between this apparent redundancy, the multi-dentate nature of heparin and HS polysaccharide chains, their involvement in protein networks and the multiple binding sites on proteins, each possessing different properties, will also be considered. Finally, the role of cations in modulating HS/heparin activity will be reviewed and some of the implications for structure–activity relationships and regulation will be discussed.

Download Full-text