Periostin promotes arterial calcification through PPARγ-related glucose metabolism reprogramming

2021 ◽  
Author(s):  
Yi Zhu ◽  
Jing-Jing Ji ◽  
Xiao-Dong Wang ◽  
Xue-Jiao Sun ◽  
Min Li ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Ex Vivo ◽  
Matrix Gla Protein ◽  
Calcium Deposition ◽  
Arterial Calcification ◽  
Agatston Score ◽  
Respiratory Chain Complexes ◽  
Ecm Remodeling ◽  
Pparγ Agonist ◽  
Lactate Levels

Extracellular matrix (ECM) exerts a list of biological functions, contributing to almost 30% of the osteogenic process. Periostin is a secreted protein that can alter ECM remodeling in response to vascular injury. However, the functional role of periostin in vascular calcification has yet to be fully described. Ex vivo, recombinant periostin accelerated thoracic aortas calcification, increased the expression of glycolysis key enzymes, and disturbed the normal oxidative phosphorylation (OXPHOS), which could be alleviated by the peroxisome proliferation-activated receptor γ (PPARγ) agonist pioglitazone. In vascular smooth muscle cells (VSMCs), recombinant periostin promoted VSMC-osteoblastic phenotype transition and calcium deposition, and suppressed PPARγ expression. Mechanistically, recombinant periostin caused over-activation of glycolysis and mitochondrial dysfunction in VSMCs, as assessed by extracellular acidification rate (ECAR), oxygen consumption rate, and mitochondrial respiratory chain complexes activities. Targeted glycolysis inhibitors reduced mitochondrial calcium overload, apoptosis, and periostin-induced VSMCs calcification. PPARγ agonists preserved glycolysis and OXPHOS in the stimulated microenvironment, and reversed periostin-promoted VSMC calcification. Furthermore, plasma periostin, lactate, and matrix Gla protein levels were measured in 274 patients who underwent computed tomography to determine coronary artery calcium score (Agatston score). Plasma periostin and lactate levels were both linked to an Agatston score of more than zero in patients with coronary artery calcification. There is also a positive correlation between plasma periostin and lactate levels. This study suggests that downregulation of PPARγ is involved in the mechanism by which periostin accelerates arterial calcification, partly through excessive glycolysis activation and unbalanced mitochondrial homeostasis.

Abstract 021: Greater Calcium Density of Coronary Artery Plaque is Protective for Cardiovascular Events. The Multi-Ethnic Study of Atherosclerosis

Circulation ◽  
2013 ◽  
Vol 127 (suppl_12) ◽  
Author(s):  
Michael H Criqui
Keyword(s):  
Coronary Artery ◽  
Standard Deviation ◽  
Proportional Hazards Model ◽  
Hazard Ratio ◽  
Calcium Deposition ◽  
Agatston Score ◽  
Standard Deviation Increase ◽  
Density Score ◽  
Independent Association ◽  
Volume Score

Background— Coronary artery calcium (CAC) measured by computed tomography (CT) has strong predictive value for incident cardiovascular disease (CVD) events. The standard CAC score is the Agatston, which is the product of the within slice CAC plaque area and a plaque specific density factor of 1, 2, 3, or 4, summed for all CT slices. Thus, the Agatston score is weighted upward for greater CAC density. However, data from both observational studies and randomized trials suggest increased CAC density per se may be protective for CVD. Methods— In a multi-ethnic population of 3398 men and women with Agatston scores > 0 at baseline, we derived a formula using the individual Agatston scores and the volume scores to create a per participant CAC density score. We then analyzed the independent associations of CAC volume and CAC density with incident hard CVD, defined as MI, resuscitated cardiac arrest, cardiac death, stroke, or stroke death, Results— During a median of 7.6 years of follow-up, there were 265 hard CVD events, 175 of which were coronary heart disease (CHD) events. In a proportional hazards model including the General Framingham Risk Score (GFRS) and both the CAC volume and CAC density score, the CAC volume score showed a strong independent association with incident CVD, with a hazard ratio per natural log standard deviation increase of 1.62, p<.0001. Conversely, the CAC density score showed an independent association that was strongly protective for CVD, with a hazard ratio per standard deviation increase of 0.72, p<.0003. Multivariate quartile analyses showed that at any given volume score, a density score in the 4 th quartile (range 3.2 to 4.0) decreased the risk of a CVD event by 51%, p=.002. The density score showed no significant interactions with either sex or ethnicity. The addition of the volume score to the model containing the GFRS increased the area under the ROC curve (AUC) from 0.664 to 0.6869, p=.015, and further addition of the density score increased the AUC to .6994, p=.023. Separate analyses limited to CHD events showed similar results. Conclusions— At any given volume of CAC, increased density in calcified coronary plaques is protective for incident CVD, consistent with the concept that calcium deposition may increase the stability of atherosclerotic plaques. CAC scoring systems should be modified to weight downward for density rather than upward, and thus improve CVD risk prediction.

scholarly journals Association of genetic polymorphisms in the Matrix Gla Protein (MGP) gene with coronary artery disease and serum mgp levels

2019 ◽  
Vol 22 (2) ◽  
pp. 43-50
Author(s):  
S Karsli-Ceppioglu ◽  
S Yazar ◽  
Y Keskin ◽  
M Karaca ◽  
NE Luleci ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Gene Polymorphisms ◽  
Regulatory Protein ◽  
Matrix Gla Protein ◽  
Arterial Calcification ◽  
Coronary Artery Diseases ◽  
Related Gene ◽  
The Matrix ◽  
Artery Disease

AbstractMatrix Gla protein (MGP) is an important regulatory protein for inhibition of calcification in the vessel wall and cartilage. The MGP gene polymorphisms are suspected to increase the risk of extracellular calcification through altering the related gene expression and serum MGP levels. The goal of this study was to examine the correlation between rs4236 (Thr83-Ala), rs12304 (Glu60-X) and rs1800802 (T138-C) polymorphisms of the MGP gene and coronary artery calcification. Serum MGP levels of 168 subjects who had undergone coronary angiography were analyzed along with genotyping of MGP gene polymorphisms. The results indicated that serum MGP levels were significantly associated with rs4236 and rs1800802 polymorphisms of the MGP gene with the occurrence of coronary artery diseases (CAD). Allelic distributions of MGP gene polymorphisms and serum MGP levels, respectively, were not significantly interconnected with the presence of CAD. Our results revealed that serum MGP levels of CAD patients show association with rs4236 and rs1800802 polymorphisms, but serum MGP levels alone do not directly reflect the risk of CAD. The role of MGP genetic variants on formation and progression of arterial calcification should be regarded in cardiovascular diseases.

scholarly journals Brain-Derived Neurotrophic Factor, a New Predictor of Coronary Artery Calcification

2021 ◽  
Vol 27 ◽  
pp. 107602962198981
Author(s):  
Hong Jin ◽  
Jing-jing Ji ◽  
Yi Zhu ◽  
Xiao-dong Wang ◽  
Yi-ping Li ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Neurotrophic Factor ◽  
Coronary Artery Calcification ◽  
Total Cholesterol Level ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Brain Derived Neurotrophic Factor ◽  
Matrix Gla Protein ◽  
Agatston Score ◽  
Characteristic Analysis

Brain-derived neurotrophic factor (BDNF) plays a functional role in vascular endothelium homeostasis and the alleviation of atherosclerosis. Matrix gla protein (MGP) and Nε-(1-carboxymethyl)-l-lysine (CML) are both confirmed to be VC predictors. This study investigated the association between BDNF, MGP, CML and coronary artery calcification (CAC). Plasma BDNF, MGP, and CML levels were measured in 274 patients who underwent computed tomography to determine the CAC score (Agatston score). It was found that patients with CAC exhibited lower BDNF and MGP and higher CML levels than those without CAC. Plasma BDNF levels in patients with diabetes or hypertension were lower compared with the control groups. In logistic regression analysis, age, hypertension, BDNF, and MGP were independent predictors of CAC. Plasma BDNF and MGP levels were both correlated with the Agatston score even after adjustment for age, total cholesterol level, triglycerides, low-density lipoprotein level, creatinine clearance rate, and the presence of hypertension and diabetes mellitus. In 167 patients with CAC, circulating BDNF level was inversely associated with CML level and positively related to MGP level. In the receiver operating characteristic analysis for CAC, the areas under the curves for BDNF, MGP, and CML were 0.757, 0.777 and 0.653, respectively. In summary, plasma BDNF levels are associated with the Agatston score, and BDNF further predicts the occurrence of CAC.

Matrix Gla protein is associated with coronary artery calcification as assessed by electron-beam computed tomography

2004 ◽  
Vol 91 (04) ◽  
pp. 790-794 ◽  
Author(s):  
Yuji Ikari ◽  
Cees Vermeer ◽  
Paul Dissel ◽  
Kotaro Hasegawa ◽  
Atsushi Shioi ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Electron Beam ◽  
Coronary Artery ◽  
Vascular Calcification ◽  
Coronary Artery Calcification ◽  
Matrix Gla Protein ◽  
Arterial Calcification ◽  
Enzyme Linked Immunosorbent Assay ◽  
Electron Beam Computed Tomography ◽  
Increased Risk

SummaryMatrix Gla protein (MGP) is an extracellular matrix protein with wide tissue distribution. It has been demonstrated that the expression of MGP is detected not only in the normal blood vessels but also calcified atherosclerotic plaques, and that MGP deficient mice develop extensive arterial calcification. MGP is thought to be a regulator of vascular calcification. A recent clinical study demonstrates the association between polymorphisms of the MGP gene and increased risk of myocardial infarction. However, there are no reports of the relationship between serum MGP levels and coronary artery calcification (CAC). We evaluated the severity of CAC using electron-beam computed tomography (EBCT), and measured serum MGP levels by enzyme-linked immunosorbent assay in 115 subjects with suspected coronary artery disease. CAC scores were correlated with traditional risk factors, such as age, gender, hypertension, diabetes, hyperlipidemia and smoking. The serum MGP levels were lower in patients with CAC than in those without CAC (p<0.001). As the severity of CAC increased, there was a significant decrease in serum MGP levels. Serum MGP levels (U/L) were 116.7 ± 20.3, 104.9 ± 19.2, 95.2 ± 15.2 and 82.2 ± 19.7, (medians 115.5, 105.0, 94.8, and 81.9) for the subjects with normal (CAC score=0), mild (CAC score=1 to 99), moderate (CAC score=100 to 400), and severe (CAC score >400) coronary calcification, respectively. We found that serum MGP levels are inversely correlated with the severity of CAC. These data suggest a possible role for MGP in the development of vascular calcification.

scholarly journals Vitamin K supplementation and arterial calcification in dialysis: results of the double-blind, randomised, placebo-controlled RenaKvit trial

2021 ◽  
Author(s):  
Karin Levy-Schousboe ◽  
Marie Frimodt-Møller ◽  
Ditte Hansen ◽  
Christian Daugaard Peters ◽  
Krista Dybtved Kjærgaard ◽  
...  
Keyword(s):  
Vitamin K ◽  
Plasma Concentrations ◽  
Mean Difference ◽  
Matrix Gla Protein ◽  
Arterial Calcification ◽  
Group Differences ◽  
Agatston Score ◽  
Dialysis Patients ◽  
Double Blind ◽  
Active Matrix

Abstract Background Arterial calcification is associated with cardiovascular mortality in dialysis patients. Active matrix Gla-protein (MGP) is a vitamin K-dependent inhibitor of arterial calcification. Elevated plasma concentrations of inactive MGP, i.e. dephosphorylated-uncarboxylated MGP (dp-ucMGP), is prevalent in dialysis patients. MGP inactivity might contribute to arterial calcification. We investigated if vitamin K supplementation had an effect on arterial calcification in chronic dialysis patients. Methods In a two-year double-blind, placebo-controlled intervention trial, 48 dialysis patients were randomised to vitamin K (menaquinone-7 (MK-7), 360 µg daily), or placebo. MK-7 in serum and dp-ucMGP in plasma were used to assess vitamin K status. Carotid-femoral pulse wave velocity (cfPWV) and scores of coronary arterial calcification (CAC) and abdominal aorta calcification (AAC) were used to assess arterial calcification. Results Thirty-seven participants completed year one, 21 completed year two. At year two, serum MK-7 was 40-fold higher, and plasma dp-ucMGP 40% lower after vitamin K supplementation compared with placebo (mean dp-ucMGP difference: -1380 pmol/L (95% CI: -2029;-730)). There was no significant effect of vitamin K supplementation on cfPWV (mean difference at year two: 1.2 m/s (95% CI: -0.1; 2.4)). CAC Agatston score increased significantly in vitamin K supplemented participants, but not significantly different from placebo (mean difference at year two: 664 (95% CI: -554; 1881)). AAC scores increased in both groups, significantly so within the placebo group at year 1, but with no significant between-group differences. Conclusion Vitamin K supplementation improved vitamin K status, but did not hinder or modify the progression of arterial calcification in dialysis patients.

Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

2019 ◽  
Vol 133 (22) ◽  
pp. 2283-2299
Author(s):  
Apabrita Ayan Das ◽  
Devasmita Chakravarty ◽  
Debmalya Bhunia ◽  
Surajit Ghosh ◽  
Prakash C. Mandal ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Chronic Inflammation ◽  
Ex Vivo ◽  
Human Subjects ◽  
Critical Role ◽  
Atherosclerotic Cardiovascular Disease ◽  
Tnf Α ◽  
Artery Disease

Abstract The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.

scholarly journals Role of Matrix Gla Protein in the Complex Network of Coronary Artery Disease: A Comprehensive Review

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 737
Author(s):  
Marko Kumric ◽  
Josip A. Borovac ◽  
Tina Ticinovic Kurir ◽  
Dinko Martinovic ◽  
Ivan Frka Separovic ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Complex Network ◽  
Vascular Calcification ◽  
Vitamin K ◽  
Clinical Decision Making ◽  
Large Body ◽  
Matrix Gla Protein ◽  
Artery Disease

Coronary artery disease (CAD) is widely recognized as one of the most important clinical entities. In recent years, a large body of accumulated data suggest that coronary artery calcification, a process highly prevalent in patients with CAD, occurs via well-organized biologic processes, rather than passively, as previously regarded. Matrix Gla protein (MGP), a vitamin K-dependent protein, emerged as an important inhibitor of both intimal and medial vascular calcification. The functionality of MGP hinges on two post-translational modifications: phosphorylation and carboxylation. Depending on the above-noted modifications, various species of MGP may exist in circulation, each with their respective level of functionality. Emerging data suggest that dysfunctional species of MGP, markedly, dephosphorylated-uncarboxylated MGP, might find its application as biomarkers of microvascular health, and assist in clinical decision making with regard to initiation of vitamin K supplementation. Hence, in this review we summarized the current knowledge with respect to the role of MGP in the complex network of vascular calcification with concurrent inferences to CAD. In addition, we discussed the effects of warfarin use on MGP functionality, with concomitant implications to coronary plaque stability.

scholarly journals A Multilayer Functionalized Drug-Eluting Balloon for Treatment of Coronary Artery Disease

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 614
Author(s):  
Hak-Il Lee ◽  
Won-Kyu Rhim ◽  
Eun-Young Kang ◽  
Bogyu Choi ◽  
Jun-Hyeok Kim ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Ex Vivo ◽  
Multilayer Coating ◽  
Balloon Catheter ◽  
Transition Time ◽  
Coating Materials ◽  
Drug Transfer ◽  
Coated Materials ◽  
Drug Loss ◽  
Drug Eluting

Drug-eluting balloons (DEBs) have been mostly exploited as an interventional remedy for treating atherosclerosis instead of cardiovascular stents. However, the therapeutic efficacy of DEB is limited due to their low drug delivery capability to the disease site. The aim of our study was to load drugs onto a balloon catheter with preventing drug loss during transition time and maximizing drug transfer from the surface of DEBs to the cardiovascular wall. For this, a multilayer-coated balloon catheter, composed of PVP/Drug-loaded liposome/PVP, was suggested. The hydrophilic property of 1st layer, PVP, helps to separate drug layer in hydrophilic blood vessel, and the 2nd layer with Everolimus (EVL)-loaded liposome facilitates drug encapsulation and sustained release to the targeted lesions during inflation time. Additionally, a 3rd layer with PVP can protect the inner layer during transition time for preventing drug loss. The deionized water containing 20% ethanol was utilized to hydrate EVL-loaded liposome for efficient coating processes. The coating materials showed negligible toxicity in the cells and did not induce pro-inflammatory cytokine in human coronary artery smooth muscle cells (HCASMCs), even in case of inflammation induction through LPS. The results of hemocompatibility for coating materials exhibited that protein adsorption and platelet adhesion somewhat decreased with multilayer-coated materials as compared to bare Nylon tubes. The ex vivo experiments to confirm the feasibility of further applications of multilayer-coated strategy as a DEB system demonstrated efficient drug transfer of approximately 65% in the presence of the 1st layer, to the tissue in 60 s after treatment. Taken together, a functional DEB platform with such a multilayer coating approach would be widely utilized for percutaneous coronary intervention (PCI).

scholarly journals Myorelaxant Effect of the Dysphania ambrosioides Essential Oil on Sus scrofa domesticus Coronary Artery and Its Toxicity in the Drosophila melanogaster Model

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 2041
Author(s):  
Luiz Jardelino de Lacerda Neto ◽  
Andreza Guedes Barbosa Ramos ◽  
Renata Evaristo Rodrigues da Silva ◽  
Luís Pereira-de-Morais ◽  
Fernanda Maria Silva ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Essential Oil ◽  
Coronary Arteries ◽  
Sus Scrofa ◽  
Ex Vivo ◽  
Alternative Methods ◽  
Major Constituent ◽  
Sus Scrofa Domesticus

Purpose: Alternative methods for the use of animals in research have gained increasing importance, due to assessments evaluating the real need for their use and the development of legislation that regulates the subject. The principle of the 3R’s (replacement, reduction and refinement) has been an important reference, such that in vitro, ex vivo and cord replacement methods have achieved a prominent place in research. Methods: Therefore, due to successful results from studies developed with these methods, the present study aimed to evaluate the myorelaxant effect of the Dysphania ambrosioides essential oil (EODa) using a Sus scrofa domesticus coronary artery model, and the toxicity of both the Dysphania ambrosioides essential oil and its major constituent, α-terpinene, against Drosophila melanogaster in toxicity and negative geotaxis assays. Results: The EODa relaxed the smooth muscle of swine coronary arteries precontracted with K+ and 5-HT in assays using Sus scrofa domesticus coronary arteries. The toxicity results presented LC50 values of 1.546 mg/mL and 2.282 mg/mL for the EODa and α-terpinene, respectively, thus showing the EODa and α-terpinene presented toxicity to these dipterans, with the EODa being more toxic. Conclusions: Moreover, the results reveal the possibility of using the EODa in vascular disease studies since it promoted the relaxation of the Sus scrofa domesticus coronary smooth muscle.

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