adrenomedullin and Vascular-Calcification

Cardiovascular disease (CVD) risk screening is performed by multivariate methods relying on calculators derived from the Framingham study, other epidemiological studies or primary care records. However, it only identifies 70% of individuals at risk for CVD events and there has been interest in adding other risk factors to improve its predictive capacity. The addition of a family history of premature CVD is well established and there is evidence for adding lipoprotein (a) in some populations and possibly C-reactive protein may be suitable for general use in CVD risk assessment. Most new biochemical and imaging markers have been assessed in the context of improving risk classification in intermediate-risk groups rather than in the general population. There is evidence that N-terminal pro-B-type natriuretic peptide and coronary artery calcium score add significantly to risk prediction. The data for carotid intima-media thickness, ankle-brachial index are less strong and high sensitivity troponins look promising, but have had only limited data to date. Large scale meta-analyses ideally of pooled primary patient data will be required to determine the best additional markers to add to conventional risk prediction and in what groups to apply them.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adrenomedullin; Ankle Brachial Index; Arginine; Biomarkers; Blood Flow Velocity; C-Reactive Protein; Cardiovascular Diseases; Carotid Intima-Media Thickness; Early Diagnosis; Humans; Lipoprotein(a); Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; Risk Assessment; Troponin; Vascular Calcification; Vasodilation

Vascular calcification (VC) is regarded as an independent risk factor for cardiovascular events in type 2 diabetic patients. Glucose transporter 1 (GLUT1) involves VC. Intermedin/Adrenomedullin-2 (IMD/ADM2) is a cardiovascular protective peptide that can inhibit multiple disease-associated VC. However, the role and mechanism of IMD in diabetic VC remain unclear. Here, we investigated whether IMD inhibits diabetic VC by inhibiting GLUT1.. These findings revealed that IMD exerted its anti-calcification effect by inhibiting GLUT1, providing a novel therapeutic target for diabetic VC.

Topics: Adrenomedullin; Animals; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fructose; Glucose Transporter Type 1; Glycation End Products, Advanced; Humans; Mice; Myocytes, Smooth Muscle; Peptide Hormones; Rats; Signal Transduction; Vascular Calcification

Vascular calcification is a major risk factor for cardiovascular disease and accounts for a large proportion of deaths from cardiovascular disease in patients with chronic kidney disease. The high incidence, rapid progression and irreversibility of vascular smooth muscle cell (VSMC) calcification in patients has attracted attention. In the present study, the effect of intermedin1‑47 (IMD1‑47), an important isoform of intermedin, was investigated on the calcification of rat cardiovascular VSMCs induced by high phosphate (HP). To stimulate osteoblast‑like differentiation and calcification in rat VSMCs, 10 mM β‑sodium glycerophosphate was used. The VSMCs were then treated with three doses of IMD1‑47 and the effects of IMD1‑47 on VSMC calcification, on the expression of osteogenic markers [osteoprotegerin, Runt‑related transcription factor 2 (Runx2) and osteopontin (OPN)] and on alkaline phosphatase (ALP) activity were assessed. HP treatment significantly enhanced the cellular calcium content of VSMCs, the expression of osteogenic markers, and ALP activity, while IMD1‑47 significantly reversed these effects in a dose‑dependent manner. The protein expression levels of Wnt1, Wnt3a and active β‑catenin were determined and it was found that IMD1‑47 significantly inhibited their expression. Following β‑catenin silencing, the protein expression levels Runx2 and OPN were increased compared with the IMD1‑47 treatment alone, indicating a role for the Wnt/β‑catenin pathway in the effects of IMD1‑47 on osteogenic markers. The present study suggested that IMD1‑47 inhibited HP‑induced VSMC calcification by regulating the Wnt/β‑catenin signaling pathway.

Topics: Adrenomedullin; Animals; beta Catenin; Calcification, Physiologic; Core Binding Factor Alpha 1 Subunit; Glycerophosphates; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neuropeptides; Osteogenesis; Osteopontin; Phosphates; Rats; Rats, Sprague-Dawley; Vascular Calcification; Wnt Signaling Pathway; Wnt1 Protein; Wnt3A Protein

We previously reported that endoplasmic reticulum (ER) stress-mediated apoptosis participated in vascular calcification. Importantly, a novel paracrine/autocrine peptide intermedin1-53 (IMD1-53) in the vasculature inhibited vascular calcification in rats. But the mechanisms needed to be fully elucidated. Vascular smooth muscle cells (VSMCs) calcification was induced by CaCl2 and β-glycerophosphate. Tunicamycin (Tm) or dithiothreitol (DTT) was used to induce ER stress. We found that IMD1-53 (10(-7)mol/L) treatment significantly alleviated the protein expression of ER stress hallmarks activating transcription factor 4 (ATF4), ATF6, glucose-regulated protein 78 (GRP78) and GRP94 induced by Tm or DTT. ER stress occurred in early and late calcification of VSMCs but was inhibited by IMD1-53. These inhibitory effects of IMD1-53 were abolished by treatment with the protein kinase A (PKA) inhibitor H89. Pretreatment with IMD1-53 decreased the number of apoptotic VSMCs and downregulated protein expression of cleaved caspase 12 and C/EBP homologous protein (CHOP) in calcified VSMCs. Concurrently, IMD1-53 restored the loss of VSMC lineage markers and ameliorated calcium deposition and alkaline phosphatase activity in calcified VSMCs as well. The observation was further verified by Alizarin Red S staining, which showed that IMD1-53 reduced positive red nodules among calcified VSMCs. In conclusion, IMD1-53 attenuated VSMC calcification by inhibiting ER stress through cAMP/PKA signalling.

Topics: Adrenomedullin; Animals; Apoptosis; Calcinosis; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Endoplasmic Reticulum Stress; Male; Muscle, Smooth, Vascular; Neuropeptides; Rats; Rats, Sprague-Dawley; Signal Transduction; Vascular Calcification

To determine the therapeutic effects of adrenomedullin (ADM) on vascular calcification and related molecular mechanism in fructose-induced insulin resistance rats.. Rats received ordinary drinking water or 10% fructose in drinking water for 12 weeks and subcutaneous injection of normal saline or ADM (3.6 μg kg(-1) ) twice a day for the last 4 weeks. Levels of ADM, calcitonin receptor-like receptors (CRLR), receptor activity-modifying proteins (RAMP) as well as calcium content, alkaline phosphatase (ALP) activity, osteoblastic and contractile smooth muscle markers in aortic media were measured.. The levels of ADM, CRLR, RAMP2 and RAMP3 in aortic media were increased in fructose-fed rats. ADM treatment attenuated the fructose-induced insulin resistance, increased blood pressure, fasting glucose, insulin, triglycerides and cholesterol levels. It improved VSMCs proliferation and disordered arrangement and hyperplasia of elastic fibres in fructose-fed rats. Calcium deposits, calcium content and ALP activity in the aortic media were increased in fructose-fed rats, which were attenuated by ADM treatment. The osteoblastic markers such as osteopontin (OPN), bone morphogenetic protein 2 (BMP2) proteins and core binding factor alpha-1 (Cbfα-1) protein and mRNA expressions were increased in fructose-fed rats. ADM treatment increased the OPN protein expression, but reduced the BMP2 protein, Cbfα-1 protein and mRNA expression. Contractile smooth muscle markers such as α-actin and smooth muscle 22α (SM-22α) were downregulated in fructose-fed rats, which were recovered by ADM treatment.. Administration of ADM attenuates insulin resistance, calcium deposition and osteogenic transdifferentiation in aortic media in fructose-fed rats.

Topics: Adrenomedullin; Animals; Aorta; Biomarkers; Blood Glucose; Blood Pressure; Cell Transdifferentiation; Cholesterol; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Fructose; Insulin; Insulin Resistance; Male; Osteogenesis; Rats; Rats, Sprague-Dawley; Signal Transduction; Triglycerides; Vascular Calcification

Topics: Adrenomedullin; Animals; Aorta; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Insulin Resistance; Male; Vascular Calcification

Midregional proadrenomedullin (MR-proADM) is elevated in patients with heart failure and myocardial infarction. The aim of this study was to evaluate the association of MR-proADM with the grade of coronary artery stenosis, presence of coronary artery soft plaques and coronary artery calcification score (CACS), determined by 64-multislice computed tomography (MSCT) in patients without known prior cardiovascular disease. This retrospective study included 107 patients undergoing MSCT for confirmation (or exclusion) of coronary artery disease. MR-proADM levels were measured in all patients. The assessment of coronary artery stenoses, CACS and soft coronary plaques was made by MSCT using known criteria. The MR-proADM [median (25th-75th percentiles)] level was 0.33 (0.21-0.43) nmol/l. The MR-proADM level was 0.28 (0.22-0.40) nmol/l in patients with coronary stenoses ≥50% (n = 23) versus 0.33 (0.27-0.40) nmol/l in patients with coronary stenoses <50% (n = 83, P = 0.59), 0.33 (0.26-0.40) nmol/l in patients with soft plaques (n = 56) versus 0.33 (0.25-0.41) nmol/l in patients without soft plaques (n = 50, P = 0.73) and 0.33 (0.25-0.39) nmol/l in patients with CACS <200 (n = 81) versus 0.32 (0.26-0.44) nmol/l in patients with CACS ≥200 (n = 26, P = 0.77). In multivariate analysis, the MR-proADM level was a significant correlate of coronary artery stenoses [odds ratio (OR) = 0.93; 95% confidence interval (CI) 0.86-0.99; P = 0.026] and soft plaques (OR = 0.94; 95% CI 0.90-0.99; P = 0.015) but not of CACS (OR = 0.98; 95% CI 0.93-1.03; P = 0.36). A decreased MR-proADM level is an independent correlate of the presence of coronary artery disease and of soft atherosclerotic plaques. Patients with decreased MR-proADM levels may need invasive examinations to diagnose more severe forms of coronary artery disease.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Biomarkers; Chi-Square Distribution; Coronary Angiography; Coronary Artery Disease; Coronary Stenosis; Coronary Vessels; Down-Regulation; Female; Germany; Humans; Logistic Models; Male; Middle Aged; Multidetector Computed Tomography; Multivariate Analysis; Odds Ratio; Peptide Fragments; Plaque, Atherosclerotic; Predictive Value of Tests; Prognosis; Protein Precursors; Retrospective Studies; Risk Assessment; Risk Factors; ROC Curve; Severity of Illness Index; Vascular Calcification