LRP1-Dependent Endocytic Mechanism Governs the Signaling Output of the Bmp System in Endothelial Cells and in Angiogenesis

Rationale: Among the extracellular modulators of Bmp (bone morphogenetic protein) signaling, Bmper (Bmp endothelial cell precursor-derived regulator) both enhances and inhibits Bmp signaling. Recently we found that Bmper modulates Bmp4 activity via a concentration-dependent, endocytic trap-and-sink mechanism. Objective: To investigate the molecular mechanisms required for endocytosis of the Bmper/Bmp4 and signaling complex and determine the mechanism of Bmper's differential effects on Bmp4 signaling. Methods and Results: Using an array of biochemical and cell biology techniques, we report that LRP1 (LDL receptor-related protein 1), a member of the LDL receptor family, acts as an endocytic receptor for Bmper and a coreceptor of Bmp4 to mediate the endocytosis of the Bmper/Bmp4 signaling complex. Furthermore, we demonstrate that LRP1-dependent Bmper/Bmp4 endocytosis is essential for Bmp4 signaling, as evidenced by the phenotype of lrp1-deficient zebrafish, which have abnormal cardiovascular development and decreased Smad1/5/8 activity in key vasculogenic structures. Conclusions: Together, these data reveal a novel role for LRP1 in the regulation of Bmp4 signaling by regulating receptor complex endocytosis. In addition, these data introduce LRP1 as a critical regulator of vascular development. These observations demonstrate Bmper's ability to fine-tune Bmp4 signaling at the single-cell level, unlike the spatial regulatory mechanisms applied by other Bmp modulators.     

A giant cardiac lipoma associated with ventricular inversion and ventricular aneurysm: ultrasonography and CT imaging findings

Cardiac lipomas are rare, mostly asymptomatic, and usually found incidentally during noncardiac examinations; however, they also can be symptomatic, depending on their size and location. Here, we report a case of surgically proved pericardial lipoma that was big and for which cardiac structures were substantially altered. The combination of CT imaging and ultrasonography enabled a precise diagnosis in terms of localization, tissue characterization, and complications of the tumor. The origin of the tumor, however, remains undetermined despite a series of postoperative CT scan and ultrasound examinations.     

Accumulation of tissue advanced glycation end products correlated with glucose exposure dose and associated with cardiovascular morbidity in patients on peritoneal dialysis

ObjectivesAccumulation of tissue advanced glycation end products (AGEs) is a marker of cumulative glycemic and/or oxidative stress. Cutaneous AGEs levels measured by skin autofluorescence correlate well with cardiovascular outcomes in diabetes and hemodialysis (HD) patients. The present study aimed to compare tissue AGEs levels with peritoneal dialysis (PD) and HD patients and to evaluate the relationship between skin autofluorescence and cardiovascular morbidity in patients on PD.MethodsA total of 2388 maintenance dialysis patients (613 PD and 1775 HD) were enrolled in this cross-sectional study. Skin autofluorescence was measured non-invasively with an autofluorescence reader. Cardiovascular morbidity was defined as clinically diagnosed ischemic heart disease, heart failure, stroke or peripheral vascular disease from initiation of dialysis.ResultsMore than 90% of patients on both PD and HD had met current dialysis adequacy targets. Compared to HD group, PD patients receiving conventional glucose-containing dialyzate had significantly higher skin autofluorescence values in each category of age and dialysis duration, irrespective of the presence or absence of diabetes. In PD patients, skin autofluorescence values were strongly correlated with the duration of PD and glucose exposure dose and independently associated with cardiovascular morbidity. Multivariate analysis revealed that glucose exposure dose and skin autofluorescence were the strongest risk factors for cardiovascular morbidity in PD patients after adjustment by age, gender, and other classic- or uremic-related risk factors.ConclusionsAccumulation of tissue AGEs provides a potential link between PD exposure of metabolic stress and progression of cardiovascular disease in patients on PD.     

Targeting protein-trafficking pathways alters melanoma treatment sensitivity

Protein-trafficking pathways are targeted here in human melanoma cells using methods independent of oncogene mutational status, and the ability to up-regulate and down-regulate tumor treatment sensitivity is demonstrated. Sensitivity of melanoma cells to cis-diaminedichloroplatinum II (cDDP, cis-platin), carboplatin, dacarbazine, or temozolomide together with velaparib, an inhibitor of poly (ADP ribose) polymerase 1, is increased by up to 10-fold by targeting genes that regulate both protein trafficking and the formation of melanosomes, intracellular organelles unique to melanocytes and melanoma cells. Melanoma cells depleted of either of the protein-trafficking regulators vacuolar protein sorting 33A protein (VPS33A) or cappuccino protein (CNO) have increased nuclear localization of cDDP, increased nuclear DNA damage by platination, and increased apoptosis, resulting in increased treatment sensitivity. Depleted cells also exhibit a decreased proportion of intracellular, mature melanosomes compared with undepleted cells. Modulation of protein trafficking via cell-surface signaling by binding the melanocortin 1 receptor with the antagonist agouti-signaling protein decreased the proportion of mature melanosomes formed and increased cDDP sensitivity, whereas receptor binding with the agonist melanocyte-stimulating hormone resulted in an increased proportion of mature melanosomes formed and in decreased sensitivity (i.e., increased resistance) to cDDP. Mutation of the protein-trafficking gene Hps6, known to impair the formation of mature melanosomes, also increased cDDP sensitivity. Together, these results indicate that targeting protein-trafficking molecules markedly increases melanoma treatment sensitivity and influences the degree of melanosomes available for sequestration of therapeutic agents.