Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells

Vascular calcification resulting from hyperphosphatemia is a major determinant of mortality in chronic kidney disease (CKD). Vascular calcification is driven by aldosterone-sensitive osteogenic transformation of vascular smooth muscle cells (VSMCs). We show that even in absence of exogenous aldosterone, silencing and pharmacological inhibition (spironolactone, eplerenone) of the mineralocorticoid receptor (MR) ameliorated phosphate-induced osteo-/chondrogenic transformation of primary human aortic smooth muscle cells (HAoSMCs). High phosphate concentrations up-regulated aldosterone synthase (CYP11B2) expression in HAoSMCs. Silencing and deficiency of CYP11B2 in VSMCs ameliorated phosphate-induced osteogenic reprogramming and calcification. Phosphate treatment was followed by nuclear export of APEX1, a CYP11B2 transcriptional repressor. APEX1 silencing up-regulated CYP11B2 expression and stimulated osteo-/chondrogenic transformation. APEX1 overexpression blunted the phosphate-induced osteo-/chondrogenic transformation and calcification of HAoSMCs. Cyp11b2 expression was higher in aortic tissue of hyperphosphatemic klotho-hypomorphic (kl/kl) mice than in wild-type mice. In adrenalectomized kl/kl mice, spironolactone treatment still significantly ameliorated aortic osteoinductive reprogramming. Our findings suggest that VSMCs express aldosterone synthase, which is up-regulated by phosphate-induced disruption of APEX1-dependent gene suppression. Vascular CYP11B2 may contribute to stimulation of VSMCs osteo-/chondrogenic transformation during hyperphosphatemia

Thermic sealing in femoral catheterization: First experience with the Secure Device

Background: Devices currently used to achieve hemostasis of the femoral artery following percutaneous cardiac catheterization are associated with vascular complications and remnants of artificial materials are retained at the puncture site. The Secure arterial closure Device induces hemostasis by utilizing thermal energy, which causes collagen shrinking and swelling. In comparison to established devices, it has the advantage of leaving no foreign material in the body following closing. This study was designed to evaluate the efficacy and safety of the Secure Device to close the puncture site following percutaneous cardiac catheterization. Methods: The Secure Device was evaluated in a prospective non-randomized single-center trial with patients undergoing 6 F invasive cardiac procedures. A total of 67 patients were enrolled and the device was utilized in 63 patients. Fifty diagnostic and 13 interventional cases were evaluated. Femoral artery puncture closure was performed immediately after completion of the procedure. Time to hemostasis (TTH), time to ambulation (TTA) and data regarding short-term and 30-day clinical follow-up were recorded. Results: Mean TTH was 4:30 ± 2:15 min in the overall observational group. A subpopulation of patients receiving anticoagulants had a TTH of 4:53 ± 1:43 min. There were two access site complications (hematoma > 5 cm). No major adverse events were identified during hospitalization or at the 30 day follow-up. Conclusions: The new Secure Device demonstrates that it is feasible in diagnostic and interventional cardiac catheterization. With respect to safety, the Secure Device was non-inferior to other closure devices as tested in the ISAR closure trial

CaMKII delta C Drives Early Adaptive Ca(2+)Change and Late Eccentric Cardiac Hypertrophy

Rationale: CaMKII (Ca2+-Calmodulin dependent protein kinase) delta C activation is implicated in pathological progression of heart failure (HF) and CaMKII delta C transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca(2+)handling and CaMKII activation in hypertrophy and HF. Objective: To measure time- and location-dependent activation of CaMKII delta C signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKII delta C transgenic mice. Methods and Results: We used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKII delta-knockout), CaMKII delta C transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKII delta C activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKII delta activation caused a compensatory increase in sarcoplasmic reticulum Ca(2+)content, Ca(2+)transient amplitude, and [Ca2+] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKII delta TG mice (6-8 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11-13 weeks, respectively), during which time the compensatory Ca(2+)transient effects reversed, but further increases in nuclear and time-averaged [Ca2+] and CaMKII activation occurred. CaMKII delta TG mice lacking delta B exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKII delta expression, especially for CaMKII delta C in nuclear fractions. Conclusions: We conclude that in early TAC perinuclear CaMKII delta C activation promotes adaptive increases in myocyte Ca(2+)transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca2+-CaMKII delta C axis contributes to eccentric hypertrophy and HF

Anterior ischemic optic neuropathy in pediatric peritoneal dialysis: risk factors and therapy

Sudden blindness caused by anterior ischemic optic neuropathy (AION) is a rare complication for patients undergoing peritoneal dialysis (PD). Prognosis is generally poor, with AION commonly resulting in permanent visual loss

Early remodeling of perinuclear Ca2+ stores and nucleoplasmic Ca2+ signaling during the development of hypertrophy and heart failure.

BackgroundA hallmark of heart failure is impaired cytoplasmic Ca(2+) handling of cardiomyocytes. It remains unknown whether specific alterations in nuclear Ca(2+) handling via altered excitation-transcription coupling contribute to the development and progression of heart failure.Methods and resultsUsing tissue and isolated cardiomyocytes from nonfailing and failing human hearts, as well as mouse and rabbit models of hypertrophy and heart failure, we provide compelling evidence for structural and functional changes of the nuclear envelope and nuclear Ca(2+) handling in cardiomyocytes as remodeling progresses. Increased nuclear size and less frequent intrusions of the nuclear envelope into the nuclear lumen indicated altered nuclear structure that could have functional consequences. In the (peri)nuclear compartment, there was also reduced expression of Ca(2+) pumps and ryanodine receptors, increased expression of inositol-1,4,5-trisphosphate receptors, and differential orientation among these Ca(2+) transporters. These changes were associated with altered nucleoplasmic Ca(2+) handling in cardiomyocytes from hypertrophied and failing hearts, reflected as increased diastolic Ca(2+) levels with diminished and prolonged nuclear Ca(2+) transients and slowed intranuclear Ca(2+) diffusion. Altered nucleoplasmic Ca(2+) levels were translated to higher activation of nuclear Ca(2+)/calmodulin-dependent protein kinase II and nuclear export of histone deacetylases. Importantly, the nuclear Ca(2+) alterations occurred early during hypertrophy and preceded the cytoplasmic Ca(2+) changes that are typical of heart failure.ConclusionsDuring cardiac remodeling, early changes of cardiomyocyte nuclei cause altered nuclear Ca(2+) signaling implicated in hypertrophic gene program activation. Normalization of nuclear Ca(2+) regulation may therefore be a novel therapeutic approach to prevent adverse cardiac remodeling