Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0007222 (cardiovascular disease)
 65,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence suggests that PTHrP [PTH (parathyroid hormone)-related protein] can act as an inflammatory mediator in several pathological settings including cardiovascular disease. The aim of the present study was to determine whether PTHrP might be involved in human platelet activation. We used a turbidimetric method to determine platelet aggregation. The expression of PTH1R (PTH type 1 receptor) in human platelets was analysed by Western blot and flow cytometry analyses. PTHrP-(1-36) (10(-7) mol/l) by itself failed to modify the activation of platelets. However, it significantly enhanced ADP-induced platelet activation, and also increased the ability of other agonists (thrombin, collagen and arachidonic acid) to induce platelet aggregation. H89 (10(-6) mol/l) and 25 x 10(-6) mol/l Rp-cAMPS (adenosine 3',5'-cyclic monophosphorothioate Rp-isomer), two protein kinase A inhibitors, and 25 x 10(-9) mol/l bisindolylmaleimide I, a protein kinase C inhibitor, partially decreased the enhancing effect of PTHrP-(1-36) on ADP-induced platelet activation. Meanwhile, 10(-6) mol/l PTHrP-(7-34), a PTH1R antagonist, as well as 10(-5) mol/l PD098059, a MAPK (mitogen-activated protein kinase) inhibitor, or a farnesyltransferase inhibitor abolished this effect of PTHrP-(1-36). Moreover, 10(-7) mol/l PTHrP-(1-36) increased (2-fold over control) MAPK activation in human platelets. PTH1R was detected in platelets, and the number of platelets expressing it on their surface in patients during AMI (acute myocardial infarction) was not different from that in a group of patients with similar cardiovascular risk factors without AMI. Western blot analysis showed that total PTH1R protein levels were markedly higher in platelets from control than those from AMI patients. PTH1R was found in plasma, where its levels were increased in AMI patients compared with controls. In conclusion, human platelets express the PTH1R. PTHrP can interact with this receptor to enhance human platelet activation induced by several agonists through a MAPK-dependent mechanism.
 ...
PMID:Effect of parathyroid-hormone-related protein on human platelet activation. 1750 18

Cardiovascular disease, such as atherosclerosis, has been associated with reduced bone mineral density and fracture risk. A major etiologic factor in atherogenesis is believed to be oxidized phospholipids. We previously found that these phospholipids inhibit spontaneous osteogenic differentiation of marrow stromal cells, suggesting that they may account for the clinical link between atherosclerosis and osteoporosis. Currently, anabolic agents that promote bone formation are increasingly used as a new treatment for osteoporosis. It is not known, however, whether atherogenic phospholipids alter the effects of bone anabolic agents, such as bone morphogenetic protein (BMP)-2 and parathyroid hormone (PTH). Therefore we investigated the effects of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (ox-PAPC) on osteogenic signaling induced by BMP-2 and PTH in MC3T3-E1 cells. Results showed that ox-PAPC attenuated BMP-2 induction of osteogenic markers alkaline phosphatase and osteocalcin. Ox-PAPC also inhibited both spontaneous and BMP-induced expression of PTH receptor. Consistently, pretreatment of cells with ox-PAPC inhibited PTH-induced cAMP production and expression of immediate early genes Nurr1 and IL-6. Results from immunofluorescence and Western blot analyses showed that inhibitory effects of ox-PAPC on BMP-2 signaling were associated with inhibition of SMAD 1/5/8 but not p38-MAPK activation. These effects appear to be due to ox-PAPC activation of the ERK pathway, as the ERK inhibitor PD98059 reversed ox-PAPC inhibitory effects on BMP-2-induced alkaline phosphatase activity, osteocalcin expression, and SMAD activation. These results suggest that atherogenic lipids inhibit osteogenic signaling induced by BMP-2 and PTH, raising the possibility that hyperlipidemia and atherogenic phospholipids may interfere with anabolic therapy.
 ...
PMID:Atherogenic phospholipids attenuate osteogenic signaling by BMP-2 and parathyroid hormone in osteoblasts. 1752 49

Vitamin D deficiency is associated with cardiovascular disease, the most common cause of mortality in hemodialysis patients. To investigate the relation between blood levels of 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) with hemodialysis outcomes, we measured baseline vitamin D levels in a cross-sectional analysis of 825 consecutive patients from within a prospective cohort of incident US hemodialysis patients. Of these patients, 78% were considered vitamin D deficient with 18% considered severely deficient. Calcium, phosphorus, and parathyroid hormone levels correlated poorly with 25D and 1,25D concentrations. To test the association between baseline vitamin D levels and 90-day mortality, we selected the next 175 consecutive participants who died within 90 days and compared them to the 750 patients who survived in a nested case-control analysis. While low vitamin D levels were associated with increased mortality, significant interaction was noted between vitamin D levels, subsequent active vitamin D therapy, and survival. Compared to patients with the highest 25D or 1,25D levels who received therapy, untreated deficient patients were at significantly increased risk for early mortality. Our study shows that among incident hemodialysis patients, vitamin D deficiency is common, correlates poorly with other components of mineral metabolism and is associated with increased early mortality.
 ...
PMID:Vitamin D levels and early mortality among incident hemodialysis patients. 1862 98

Secondary hyperparathyroidism (SHPT) is a common and serious consequence of chronic kidney disease (CKD). SHPT is a complex condition characterised by a decline in 1,25-dihydroxyvitamin D and consequent vitamin D receptor (VDR) activation, abnormalities in serum calcium and phosphorus levels, parathyroid gland hyperplasia, elevated parathyroid hormone (PTH) secretion, and systemic mineral and bone abnormalities. There are three classes of drugs used for treatment of SHPT: (i) nonselective VDR activators or agonists (VDRAs); (ii) selective VDRAs; and (iii) calcimimetics. The VDRAs act on the VDR, whereas the calcimimetics act on the calcium-sensing receptor. Calcimimetics are commonly used in conjunction with VDRA therapy. By virtue of the differences in their chemical structure, the nonselective and selective VDRAs differ in their effects on gene expression, and ultimately parathyroid gland, bone and intestine function. Medications in all three classes are effective in suppression of PTH; however, clinical studies show that calcimimetics are associated with an unfavourable tolerability profile and hypocalcaemia, whereas nonselective VDRAs, and to a lesser extent selective VDRAs, are associated with dose-limiting hypercalcaemia and hyperphosphataemia. Selective VDRAs also have minimal undesirable effects on calcium absorption in the intestine, and calcium and phosphorus mobilisation in the bone compared with nonselective VDRAs. Calcium load in patients with CKD can lead to vascular calcification, accelerated progression of cardiovascular disease and increased mortality. High serum phosphorus levels are also associated with adverse effects on cardiorenal function and survival. Recent evidence suggests that VDRAs are associated with a survival benefit in CKD patients, with a more favourable effect with selective VDRAs than nonselective VDRAs. Paricalcitol, a selective VDRA, is reported to exert specific effects on gene expression in various cell types that are involved in vascular calcification and the development of coronary artery disease. This article examines the molecular mechanisms that determine selectivity of VDRAs, and reviews the evidence for clinical efficacy, safety and survival associated with the three drug classes used for treatment of SHPT in CKD patients.
 ...
PMID:Vitamin D receptor activator selectivity in the treatment of secondary hyperparathyroidism: understanding the differences among therapies. 1788 83

The information available in the literature regarding pulmonary hypertension (PH) in peritoneal dialysis (PD) patients is limited. The objective of the present study was to examine the prevalence and characteristics of PH in PD patients. We retrospectively collected the clinical profile, echocardiographic (ECHO) findings, and biochemical data for 36 PD patients for which ECHO findings were available. We compared characteristics between patients with and without PH. We found PH, defined as pulmonary arterial pressure (PAP) > or = 35 mmHg, in 15 patients. The prevalence of PH was 42%. Mean age (+/- standard deviation) of the patients with and without PH was 58 +/- 15 years and 52 +/- 15 years respectively (p = 0.30). Mean PAP of the PH patients was 43.8 +/- 9.0 mmHg (range: 35-65 mmHg). Patients with PH had a lower ejection fraction than did patients without PH (46.3% +/- 19.8% vs. 56.5% +/- 11.8% respectively, p = 0.07). Patients with PH also had a higher prevalence of global hypokinesia (60% vs. 29%, p = 0. 059) and dilated left ventricular chamber (53% vs. 19%, p = 0.03). In PH patients, body mass index (24 +/- 4.5 kg/m2 vs. 28 +/- 5.0 kg/m2, p = 0.024), normalized protein catabolic rate (0. 78 +/- 0.21 g/kg vs. 0.95 +/- 0.27 g/kg daily, p = 0.049), and ferritin (226 +/- 210 ng/mL vs. 873 +/- 965 ng/mL, p = 0.005) were significantly lower and lactate dehydrogenase was higher (264 +/- 99 U/L vs. 206 +/- 79 U/L, p = 0.06) than in patients without PH. We observed no significant differences in race or sex, incidence of hypertension or cardiovascular disease, or vitamin D analog use between the two groups of patients. During the study period, 60% of PH patients and 38% of patients without PH died (p = 0.19). Values of PAP correlated directly with serum levels of phosphorus (r = 0.44, p = 0.02), CaxP product (r = 0.40, p = 0.04), and parathyroid hormone (r = 0.42, p = 0.03). Of continuous ambulatory PD and continuous cycling PD patients, 21% and 55% respectively had PH (p = 0. 049). In PD patients, PH is highly prevalent and may be associated with higher mortality risk.
 ...
PMID:Pulmonary hypertension in peritoneal dialysis patients. 1788 18

Abnormal bone in chronic kidney disease (CKD) may adversely affect vascular calcification via disordered calcium and phosphate metabolism. In this context, bone health should be viewed as a prerequisite for the successful prevention/treatment of vascular calcification (VC) along with controlled parathyroid hormone (PTH) secretion, the use of calcium-based phosphate binders and vitamin D therapy. In CKD patients, VC occurs more frequently and progresses more rapidly than in the general population, and is associated with increased cardiovascular disease (CVD) morbidity and mortality. A number of therapies aimed at reducing PTH concentration are associated with an increase of calcaemia and Ca x P product, e.g. calcium-containing phosphate binders or active vitamin D. The introduction of calcium-free phosphate binders has reduced calcium load, attenuating VC and improving trabecular bone content. In addition, a major breakthrough has been achieved through the use of calcimimetics, as first agents which lower PTH without increasing the concentrations of serum calcium and phosphate. Nowadays, it is becoming evident that even early stage CKD is recognised as an independent CVD risk factor. Moreover, the excess of CVD among dialysis patients cannot be explained entirely on the basis of abnormal mineral and bone metabolism. Hence, much controversy has surrounded the cost-effectiveness of treatment with the new phosphate-binding drugs as well as new vitamin D analogs and calcimimetics. Thus, it seems prudent and reasonable that maintaining bone health and mineral homeostasis should rely on some modifications of standard phosphate binding and calcitriol therapy. Hypophosphataemia and hypercalcaemia in adynamic bone disease (ABD) might be treated by reducing the number of calcium carbonate/acetate tablets in order to increase serum phosphate and decrease serum calcium, which, in turn, might positively stimulate PTH secretion. The same rationale is assumed for the use of a low calcium dialysate. On the other hand, secondary hyperparathyroidism with hyperphosphataemia and hypocalcaemia should be treated with a substantial number of calcium carbonate/acetate tablets in combination with calcitriol and low calcium dialysate in order to decrease serum phosphate and maintain the Ca x P product within K/DOQI guidelines (<4.4 mmol l(-1)). Finally, it becomes apparent that prevention, with judicious use of calcium-based binders, vitamin D and a low calcium dialysate without adverse effects on Ca x P or oversuppression of PTH, provides the best management of VC and mineral and bone disorder in CKD patients.
 ...
PMID:Bone health and vascular calcification relationships in chronic kidney disease. 1789 31

The mortality rate in patients with end-stage renal disease (ESRD) is extremely high, mainly because of the high prevalence of cardiovascular disease. In addition to traditional cardiovascular risk factors, other factors peculiar to chronic kidney disease play a role. Anemia and calcium-phosphate disorders are of particular interest, not only because they have been related to an increased risk of death but, more importantly, because they can be reversed by treatment, thereby providing the opportunity to prevent or delay the onset of cardiovascular disease. Despite a clear association between higher hemoglobin levels and better survival, data from interventional trials do not seem to show a significant positive effect of hemoglobin normalization with erythropoiesis-stimulating agents on survival and left ventricular mass in ESRD patients. Nevertheless, partial correction of anemia is still an important goal to be reached, as is also suggested by international guidelines. Disorders of calcium-phosphate metabolism have also been clearly related to increased mortality. Unlike anemia, which can be easily corrected by treatment in most cases, mineral metabolism is much less effectively treated. New agents, such as phosphate binders not containing calcium and aluminum, vitamin D analogs with lower calcemic activity, and calcimimetics, are becoming increasingly available in everyday clinical practice and are likely to allow a higher percentage of patients to achieve the recommended targets for calcium-phosphate and parathyroid hormone. Given that these molecules have only been introduced recently, clear data from interventional studies showing improved survival after adequate correction of mineral metabolism parameters are still lacking.
 ...
PMID:[Recent advances in the prevention of cardiovascular morbidity and mortality in end-stage renal disease: role of anemia, hyperparathyroidism and calcifications]. 1792 44

Cardiovascular disease is increasingly recognized as a life-limiting problem in young patients with chronic kidney disease, but there are few studies in children that describe its determinants. We studied the association of intact parathyroid hormone (iPTH) levels and their management on vascular structure and function in 85 children, ages 5-18 years, who had received dialysis for > or =6 months. Compared to controls, dialysis patients had increased carotid intima-media thickness and pulse-wave velocity. All vascular measures positively correlated with serum phosphorus levels, while carotid intima-media thickness and cardiac calcification score also correlated with iPTH levels. Patients with mean time-integrated iPTH levels less than twice the upper limit of normal (n = 41) had vascular measures that were comparable to age-matched controls, but those with iPTH levels greater than twice the upper limit of normal (n = 44) had greater carotid intima-media thickness, stiffer vessels, and increased cardiac calcification than controls. Patients with increased carotid intima-media thickness had stiffer vessels and a greater prevalence of cardiac calcification. There was a strong dose-dependent correlation between vitamin D and all vascular measures, and calcium intake from phosphate binders weakly correlated with carotid intima-media thickness. In conclusion, both iPTH level and dosage of vitamin D are associated with vascular damage and calcification in children on dialysis.
 ...
PMID:Mineral metabolism and vascular damage in children on dialysis. 1794 64

The bone disease that occurs as a result of chronic kidney disease (CKD) is not only debilitating but also linked to poor growth and cardiovascular disease. It is suspected that abnormal bone turnover is the main culprit for these poor outcomes. Plasma parathyroid hormone (PTH) levels are used as a surrogate marker of bone turnover, and there is a small number of studies in children that have attempted to identify the range of PTH levels that correlates with normal bone histology. It is clear that high PTH levels are associated with high bone turnover, although the range is wide. However, the ability of PTH levels to distinguish between low and normal bone turnover is less clear. This is an important issue, because current guidelines for calcium and phosphate management are based upon there being an "optimum" range for PTH. This editorial takes a critical look at the evidence upon which these recommendations are based.
 ...
PMID:What parathyroid hormone levels should we aim for in children with stage 5 chronic kidney disease; what is the evidence? 1804 47

Childhood and adolescence are crucial times for the development of a healthy skeletal and cardiovascular system. Disordered mineral and bone metabolism accompany chronic kidney disease (CKD) and present significant obstacles to optimal bone strength, final adult height, and cardiovascular health. Decreased activity of renal 1 alpha hydroxylase results in decreased intestinal calcium absorption, increased serum parathyroid hormone levels, and high-turnover renal osteodystrophy, with subsequent growth failure. Simultaneously, phosphorus retention exacerbates secondary hyperparathyroidism, and elevated levels contribute to cardiovascular disease. Treatment of hyperphosphatemia and secondary hyperparathyroidism improves growth and high-turnover bone disease. However, target ranges for serum calcium, phosphorus, and parathyroid hormone (PTH) levels vary according to stage of CKD. Since over-treatment may result in adynamic bone disease, growth failure, hypercalcemia, and progression of cardiovascular calcifications, therapy must be carefully adjusted to maintain optimal serum biochemical parameters according to stage of CKD. Newer therapeutic agents, including calcium-free phosphate binding agents and new vitamin D analogues, effectively suppress serum PTH levels while limiting intestinal calcium absorption and may provide future therapeutic alternatives for children with CKD.
 ...
PMID:Chronic kidney disease mineral and bone disorder in children. 1804 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>