Vascular Calcification: Current Genetics Underlying This Complex Phenomenon.

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vascular calcification 59 endocrinologydiseases
calcinosis 1 endocrinologydiseases
calcitriol 2 endocrinologydiseasesdrugs
diabetes mellitus 3 endocrinologydiseases
hypercalcemia 1 endocrinologydiseases
hyperparathyroidism 4 endocrinologydiseases
osteoporosis 1 endocrinologydiseases
secondary hyperparathyroidism 4 endocrinologydiseases

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calcitriol 16436 absent, a procalcification environment is promoted.Another molecule involved in vascular calcification is calcitriol (1,25-dihydroxyvitamin D), commonly used in secondary hyperparathyroidism. Especially in patients with
calcitriol 17078 indeed present excessively high levels of ectopic calcification.[[45]] Hence, this result confirms that calcitriol is an enhancer of vascular calcification.Other osteogenic induction factorsAs previously mentioned,
Select Disease Character Offset Disease Term Instance
calcinosis 20365 pseudoxanthoma,[[59]] a disease with the aforementioned characteristics, in addition to dystrophic calcinosis , which refers to calcium deposits in necrotic and inflamed spots.[[60]] A molecular link between elastic
diabetes mellitus 942 (Mönckenberg's sclerosis). Vascular calcification is also closely related to other pathologies, such as diabetes mellitus , dyslipidemia, and chronic kidney disease. It has been concluded that the degree of vascular calcification
diabetes mellitus 3110 reported that vascular calcification prevalence increases with age. Moreover, when pathologies such as diabetes mellitus , dyslipidemia, hypertension, and chronic kidney disease (CKD) are present, the mechanisms that inhibit
diabetes mellitus 25817 reported in a study, in which asymptomatic patients for coronary artery disease with the diagnosis of diabetes mellitus were analyzed. During follow-up, the incidence of myocardial infarction was 0% in the group with a coronary
hypercalcemia 16590 secondary hyperparathyroidism. Especially in patients with CKD, high levels of Vitamin D can cause hypercalcemia , which then leads to a higher risk of soft-tissue calcification.[[42]] Calcitriol increases ALP activity,[[43]]
hyperparathyroidism 14597 levels of phosphate for two main reasons: poor glomerular filtration rate and, as a result, secondary hyperparathyroidism (a common complication of CKD). Accordingly, inorganic phosphate promotes osteoblastic phenotype through
hyperparathyroidism 16501 involved in vascular calcification is calcitriol (1,25-dihydroxyvitamin D), commonly used in secondary hyperparathyroidism . Especially in patients with CKD, high levels of Vitamin D can cause hypercalcemia, which then leads
hyperparathyroidism 27644 dietary phosphate thus preventing its absorption, (7) Vitamin D receptor agonists, which treat secondary hyperparathyroidism and Vitamin D deficiency associated with CKD, (8) calcimimetics, which bind to calcium-sensing receptors
hyperparathyroidism 27788 associated with CKD, (8) calcimimetics, which bind to calcium-sensing receptors treating secondary hyperparathyroidism , (9) Vitamin K, which is a cofactor in various metabolic pathways and frequently deficient in CKD patients,
osteoporosis 27053 which take a particular relevance in CKD patients.[[96]]Many therapies used in cardiovascular disease, osteoporosis , and CKD could be promising for treating vascular calcification. Some examples are as follows: (1) the
secondary hyperparathyroidism 14587 from high levels of phosphate for two main reasons: poor glomerular filtration rate and, as a result, secondary hyperparathyroidism (a common complication of CKD). Accordingly, inorganic phosphate promotes osteoblastic phenotype through
secondary hyperparathyroidism 16491 molecule involved in vascular calcification is calcitriol (1,25-dihydroxyvitamin D), commonly used in secondary hyperparathyroidism . Especially in patients with CKD, high levels of Vitamin D can cause hypercalcemia, which then leads
secondary hyperparathyroidism 27634 binds to dietary phosphate thus preventing its absorption, (7) Vitamin D receptor agonists, which treat secondary hyperparathyroidism and Vitamin D deficiency associated with CKD, (8) calcimimetics, which bind to calcium-sensing receptors
secondary hyperparathyroidism 27778 deficiency associated with CKD, (8) calcimimetics, which bind to calcium-sensing receptors treating secondary hyperparathyroidism , (9) Vitamin K, which is a cofactor in various metabolic pathways and frequently deficient in CKD patients,
vascular calcification 1044 diabetes mellitus, dyslipidemia, and chronic kidney disease. It has been concluded that the degree of vascular calcification may vary from person to person, even if the associated pathologies and environmental factors are the
vascular calcification 1255 factors are the same. Therefore, this suggests an important genetic contribution to the development of vascular calcification . This review aimed to find the most recent evidence about vascular calcification pathophysiology regarding
vascular calcification 1336 the development of vascular calcification. This review aimed to find the most recent evidence about vascular calcification pathophysiology regarding the genetic aspects and molecular pathways.Data Sources:We conducted an exhaustive
vascular calcification 1538 Sources:We conducted an exhaustive search in Scopus, EBSCO, and PubMed with the keywords “genetics and vascular calcification ”, “molecular pathways, genetic and vascular calcification” and included the main articles from
vascular calcification 1600 PubMed with the keywords “genetics and vascular calcification”, “molecular pathways, genetic and vascular calcification ” and included the main articles from January 1995 up to August 2016. We focused on the most recent
vascular calcification 1739 the main articles from January 1995 up to August 2016. We focused on the most recent evidence about vascular calcification pathophysiology regarding the genetic aspects and molecular pathways.Study Selection:The most valuable
vascular calcification 2821 these vesicles, promoting ectopic formation of bony tissue and creating what it is generally known as vascular calcification .[[2]]Vascular calcification is the result of a deregulated mineral metabolism, which ultimately leads
vascular calcification 3021 metabolism, which ultimately leads to hydroxyapatite deposits on the vascular wall. It has been reported that vascular calcification prevalence increases with age. Moreover, when pathologies such as diabetes mellitus, dyslipidemia, hypertension,
vascular calcification 3377 vascular level are prone to be affected.[[3][4]] Therefore, in the last 20 years, the perception of vascular calcification as a pathology evoked by a passive consequence of aging has changed to the concept of an active phenomenon,
vascular calcification 4066 carotid, iliac, femoral, and aorta arteries.[[6]]From the histological standpoint, there are two types of vascular calcification . The first is the calcification of the tunica intima, also known as atherosclerotic calcification, while
vascular calcification 4770 both of these entities might share some of the same pathophysiological pathways.[[7]]The presence of vascular calcification catalyzes the deposition of new ectopic calcium in large amounts,[[3]] increasing the risks for other
vascular calcification 4989 other cardiovascular diseases and adverse cardiovascular effects.[[8]]Moreover, the linkage between vascular calcification and genetics has been confirmed by a multiethnic study, which aimed to understand the genetic basis
vascular calcification 5582 account the different aspects in which the genetic and molecular pathways are presumably involved with vascular calcification . Consequently, this review is directed to physicians and its aim is to elucidate the different associations
vascular calcification 5747 physicians and its aim is to elucidate the different associations and mechanisms that predispose to vascular calcification with a genetics scope. In addition, a brief discussion of its clinical approach in the diagnosis and
vascular calcification 5942 approach in the diagnosis and treatment has been incorporated into this work.GeneticsThe etiology of vascular calcification is multifactorial. It has been well defined that genetics plays a pivotal role in the pathogenesis of
vascular calcification 6787 normal modulation of vascular smooth muscle cell proliferation.[[10][11]] As a consequence, this causes vascular calcification , which will be explained below. In addition, other SNPs associated with CAC are located in region 6p24,
vascular calcification 7321 posttranscriptional modifications (e.g., alternative splicing), or peptide sequence, which ultimately modulate vascular calcification . According to the genetic and physiological influences, other genes have been suggested as possible
vascular calcification 7527 suggested as possible causative agents. In addition, other polymorphisms with possible associations with vascular calcification have been found. These genes have been grouped according to their mechanism of action in different categories
vascular calcification 7859 genes; in other words, both positive evidence and negative evidence regarding their association with vascular calcification have been published. Therefore, no conclusions should be drawn on this matter at the moment.[[7]]Table
vascular calcification 8008 Therefore, no conclusions should be drawn on this matter at the moment.[[7]]Table 1Genes associated with vascular calcification grouped according to their mechanism of actionCategoryGeneInfluence on endothelial function and leukocyte
vascular calcification 10520 microvasculature endothelium, and so, they are deeply involved in angiogenesis,[[19]] which is closely related to vascular calcification as explained below.The formation of new small intravascular blood vessels (angiogenesis) is common around
vascular calcification 11349 growth factor. In turn, this promotes angiogenesis and creates the particular pathways essential for vascular calcification .[[5]]Oxidative stress and cytokinesBone morphogenetic protein (BMP) molecules are known for their ectopic
vascular calcification 11538 (BMP) molecules are known for their ectopic bone formation and are recognized as important mediators of vascular calcification . BMP2 and 4 favor mineralization while BMP7 has demonstrated its ability to retard this process.[[21][22]]
vascular calcification 11987 activate a pathway of genetic transcription)[[23][24][25]] and modulate genetic expression, thus favoring vascular calcification .[[26]] On the other hand, BMP7 regulates expression of smooth muscle α-actin, preventing the osteoblastic
vascular calcification 12240 By the same token, it is suggested that polymorphisms in the BMP7 gene are associated with a higher vascular calcification risk.[[27]]While BMPs have shown to be important mediators of calcifying processes, their effects are
vascular calcification 12894 wall serves as a definite marker in the ectopic calcium deposits, generating the very first step in vascular calcification .[[5]] Cbfa1 further activates osterix, which will influence the vascular calcification phenotype. Cbfa1
vascular calcification 12981 first step in vascular calcification.[[5]] Cbfa1 further activates osterix, which will influence the vascular calcification phenotype. Cbfa1 also controls the expression of several other proteins that will promote ectopic osteoblastic
vascular calcification 13464 oxidative stress. For this reason, reactive oxygen species (ROS) can further incite other markers of vascular calcification , such as ALP activity.[[31][32][33]]BMP2 induces cyclooxygenase 2 activity and, as a result, it stimulates
vascular calcification 13833 formation. The role of BMP2 over the ROS regulation consequently provides an important link between vascular calcification and the inflammatory process, which is associated with endothelial dysfunction.[[32]] Hence, both proinflammatory
vascular calcification 13991 is associated with endothelial dysfunction.[[32]] Hence, both proinflammatory microenvironment and vascular calcification coexist in atherosclerotic lesions.[[5]]Inorganic phosphate can also activate Cbfa1. In fact, vascular
vascular calcification 15289 factor-κB ligand (RANKL), and ALP. It has been indicated that serum OPG levels are associated with vascular calcification in humans. In addition, the determination of serum OPG has been suggested as a prognostic marker of
vascular calcification 15681 smooth muscle cells, a molecular pathway that could partially explain the mechanisms underlying diabetic vascular calcification .[[39][40][41]]Medications implicated in calcificationWarfarin, a Vitamin K antagonist, is commonly used
vascular calcification 15886 antagonist, is commonly used as an oral anticoagulant to treat atherothrombotic diseases. Its use promotes vascular calcification by ultimately stopping gamma-carboxylation of MGP, an important inhibitory factor of calcification.[[5]]
vascular calcification 16410 carboxylated MGP is absent, a procalcification environment is promoted.Another molecule involved in vascular calcification is calcitriol (1,25-dihydroxyvitamin D), commonly used in secondary hyperparathyroidism. Especially
vascular calcification 17107 levels of ectopic calcification.[[45]] Hence, this result confirms that calcitriol is an enhancer of vascular calcification .Other osteogenic induction factorsAs previously mentioned, ALP activity is an important factor in the
vascular calcification 17232 calcification.Other osteogenic induction factorsAs previously mentioned, ALP activity is an important factor in the vascular calcification orchestra, because it serves as an early marker for the presence of calcium deposits. Since it is essential
vascular calcification 17674 inorganic pyrophosphate levels, an important inhibitory factor of calcification.[[46][47]]Leptin, another vascular calcification mediator, physiologically modulates bone mass, binding to and activating the ventromedial hypothalamic
vascular calcification 17950 osteoblasts.[[48][49]] In in vitro models, it has been demonstrated that leptin plays a crucial role in vascular calcification . This occurs through mechanisms[[50]] that promote osteoblast differentiation[[51]] and increase oxidative
vascular calcification 18175 oxidative stress in endothelial cells, which then induce the expression of BMP2, a well-known marker for vascular calcification .[[52][53]]Loss of mineralization inhibition factorAs previously noted, the second pathophysiologic pathway
vascular calcification 18316 mineralization inhibition factorAs previously noted, the second pathophysiologic pathway present in vascular calcification refers to the loss or malfunction of the factors that, under normal circumstances, would inhibit calcification.Pyrophosphate
vascular calcification 18703 in charge of blocking the generation of these crystals, naturally inhibiting processes that lead to vascular calcification . Hence, it is suggested that vascular calcification is a consequence of pyrophosphate regulation alterations.[[3]]Associations
vascular calcification 18755 crystals, naturally inhibiting processes that lead to vascular calcification. Hence, it is suggested that vascular calcification is a consequence of pyrophosphate regulation alterations.[[3]]Associations between ectonucleotide pyrophosphatase/phosphodiesterase
vascular calcification 19324 inheritance. This, in turn, results in a substantial decrease of serum pyrophosphate,[[54][55][56]] promoting vascular calcification .Another enzyme related to the pyrophosphate pathway is cluster of differentiation 73, a membrane surface
vascular calcification 19805 restrictive as those in ENPP1. Nonetheless, it confirms the role of ATP derivative pyrophosphate pathway in vascular calcification from a genetic perspective.[[57]]Similarly, an additional mutation related to vascular calcification
vascular calcification 19906 vascular calcification from a genetic perspective.[[57]]Similarly, an additional mutation related to vascular calcification is present in ATP-binding cassette, subfamily C, member 6 (ABCC6),[[58]] a gene that codes for a transmembrane
vascular calcification 20500 deposits in necrotic and inflamed spots.[[60]] A molecular link between elastic pseudoxanthoma and vascular calcification is established on the clinical and histological similarities between the two, suggesting that they both
vascular calcification 21241 known as calgranulins, have been identified to interact specifically in the processes that lead to vascular calcification . A direct association has been made between the expression of the S100A12 protein, or calgranulin C,
vascular calcification 21369 direct association has been made between the expression of the S100A12 protein, or calgranulin C, and vascular calcification in transgenic mice S100A12tg/ApoE deficient.[[68][69]] Vascular smooth muscle cells in those mice showed
vascular calcification 22863 its noncarboxylated form.Other inhibitory factorsThere is a great amount of other agents that inhibit vascular calcification ; we will only mention a few of them. Similar to MGP, OPN and OPG inhibit the process by acting directly
vascular calcification 23423 AssessmentThere are a number of noninvasive imaging tools that clinicians use to identify and assess vascular calcification . Nonetheless, all of them provide important information that could improve prediction of cardiovascular
vascular calcification 23634 cardiovascular risk beyond the traditional risk factors, especially in patients with CKD, in which vascular calcification is an important component of the disease.[[80]]Through a plain radiography, it is possible to recognize
vascular calcification 24949 artery calcium detection by CT scan is probably one of the most frequent and reliable methods to measure vascular calcification . Coronary artery calcium score is determined through the method of Agatston et al.,[[87][88]] an important
vascular calcification 26512 disease0–10Minimal11–100Mild101–400Moderate401–1000Severe>1000Very severeCurrent and Emerging Therapies for Vascular CalcificationThe best treatment for vascular calcification is the management of the risk factors that predispose to cardiovascular disease and the disorder of
vascular calcification 26761 metabolism. Because hydroxyapatite is insoluble and stable under physiological conditions, the treatment for vascular calcification focuses on preventing its progression.[[95]] Furthermore, several medications have been used for the
vascular calcification 26898 preventing its progression.[[95]] Furthermore, several medications have been used for the treatment of vascular calcification in humans and animal models, which take a particular relevance in CKD patients.[[96]]Many therapies
vascular calcification 27107 patients.[[96]]Many therapies used in cardiovascular disease, osteoporosis, and CKD could be promising for treating vascular calcification . Some examples are as follows: (1) the endothelin receptor antagonists, which act by reducing blood
vascular calcification 28094 calcium chelator thus preventing calcification.[[96]]ConclusionsFrom the histological point of view, vascular calcification represents a complicated, multifactor disease that can be classified as tunica intima calcium deposition
vascular calcification 28467 adverse cardiovascular events and represents a serious public health problem. The pathophysiology of vascular calcification cannot be explained by a single specific factor; rather it is the result of the association of several
vascular calcification 28683 of several genetic variants, molecular pathways interactions, and environmental factors that promote vascular calcification by either increasing osteogenesis or inhibiting its regulatory pathways. Although several molecular

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