Glucocorticoids Induce Cardiac Fibrosis via Mineralocorticoid Receptor in Oxidative Stress: Contribution of Elongation Factor Eleven-Nineteen Lysine-Rich Leukemia (ELL)

Background

Cardiac fibrosis is considered to be a crucial factor in the development of heart failure. Blockade of the mineralocorticoid receptor (MR) attenuated cardiac fibrosis and improved the prognosis of patients with chronic heart failure but the ligand for MR and the regulatory mechanism of MR pathway in the diseased heart are unclear. Here, we investigated whether glucocorticoids can promote cardiac fibrosis through MR in oxidative stress and the involvement of elongation factor eleven-nineteen lysine-rich leukemia (ELL), a co-activator of MR, in this pathway.

Methods and Results

The MR antagonist eplerenone attenuated corticosterone-induced collagen synthesis assessed by [³H]proline incorporation in rat neonatal cultured cardiac fibroblasts in the presence of H₂O₂, as an oxidative stress but not in the absence of H₂O₂. H₂O₂ increased the ELL expression levels and MR-bound ELL. ELL expression levels and MR-bound ELL were also increased in the left ventricle of heart failure model rats with significant fibrosis and enhanced oxidative stress. Eplerenone did not attenuate corticosterone-induced increase of [³H]proline incorporation in the presence of H₂O₂ after knockdown of ELL expression using small interfering RNA in cardiac fibroblasts.

Conclusion

Glucocorticoids can promote cardiac fibrosis via MR in oxidative stress, and oxidative stress modulates MR response to glucocorticoids through the interaction with ELL. Preventing cardiac fibrosis by modulating glucocorticoid-MR-ELL pathway may become a new therapeutic strategy for heart failure.     

Effects of valsartan and amlodipine on home blood pressure and cardiovascular events in Japanese hypertensive patients: a subanalysis of the VART

The Valsartan Amlodipine Randomized Trial (VART) was performed to compare the beneficial effects of valsartan and amlodipine on cardiovascular events in Japanese hypertensive patients. In this subanalysis of the VART, we assessed the relationship between home blood pressure (HBP) levels and cardiovascular events in the enrolled patients. We enrolled 1021 patients with mild-to-moderate hypertension in the VART. The participants were allocated randomly to either the valsartan group or the amlodipine group. The primary end point was a composite of all-cause death, sudden death, cerebrovascular events, cardiac events, vascular events and renal events. A total of 621 patients (valsartan group: 305 and amlodipine group: 316) completed the measurements of HBP (morning and evening) throughout the trial. Both the agents evenly and significantly lowered morning HBP and evening HBP throughout the trial. There was no significant difference in the primary end point between the two groups. However, we observed significant decreases in the left ventricular mass index and urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group. There were no significant differences in HBP levels and the main outcome of the cardiovascular events between the valsartan and amlodipine groups. However, in the valsartan group, significant improvements in left ventricular hypertrophy and microalbuminuria were observed.     

Platelet‐rich plasma protects rotator cuff‐derived cells from the deleterious effects of triamcinolone acetonide

Triamcinolone acetonide (TA) injections are widely used to treat enthesopathy, but they may induce adverse effects such as tendon impairment and rupture. Platelet‐rich plasma (PRP) is a blood fraction containing high platelet concentrations and various growth factors that play a role in tissue repair processes. The purpose of this study is to investigate whether TA has deleterious effects on human rotator cuff‐derived cells, and if PRP can protect these cells from the effects of TA. Human rotator cuff‐derived cells were cultured with and without TA and PRP, and the culture without any additive served as the control. Cell morphology was assessed at days 7 and 21. Cell viability was evaluated at days 1, 7, 14, and 21 by a water‐soluble tetrazolium salt assay. Induction of apoptosis was measured by immunofluorescence staining and flow cytometry at day 7. Induction of cleaved caspase‐3 was measured by immunofluorescence staining at day 7. The cells cultured with TA had a flattened and polygonal shape at day 7. The cells cultured with both TA and PRP were similar in appearance to control cells. Exposure to TA also significantly decreased cell viability, but cell viability did not decrease when PRP was added along with TA. The number of apoptotic cells increased with TA exposure, while addition of PRP prevented cell apoptosis. In conclusion, the deleterious effect of TA was prevented by PRP, which can be used as a protective agent for patients receiving local TA injections. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 976–982, 2013     

Cerebellar cortical-layer-specific control of neuronal migration by pituitary adenylate cyclase-activating polypeptide

Migration of immature neurons is essential for forming the cortical layers and nuclei. Impairment of migration results in aberrant neuronal cytoarchitecture, which leads to various neurological disorders. Neurons alter the mode, tempo and rate of migration when they translocate through different cortical layers, but little is known about the mechanisms underlying this process. Here we show that endogenous pituitary adenylate cyclase-activating polypeptide (PACAP) has short-term and cortical-layer-specific effects on granule cell migration in the early postnatal mouse cerebellum. Application of exogenous PACAP significantly slowed the migration of isolated granule cells and shortened the leading process in the microexplant cultures of the postnatal day (P)0-3 cerebella. Interestingly, in the cerebellar slices of P10 mice, application of exogenous PACAP significantly inhibited granule cell migration in the external granular layer (EGL) and molecular layer (ML), but failed to alter the movement in the Purkinje cell layer (PCL) and internal granular layer (IGL). In contrast, application of PACAP antagonist accelerated granule cell migration in the PCL, but did not change the movement in the EGL, ML and IGL. Inhibition of the cAMP signaling and the activity of phospholipase C significantly reduced the effects of exogenous PACAP on granule cell migration. The PACAP action on granule cell migration was transient, and lasted for approximately 2 h. The duration of PACAP action on granule cell migration was determined by the desensitization of its receptors and prolonged by inhibiting the protein kinase C. Endogenous PACAP was present sporadically in the bottom of the ML, intensively in the PCL, and throughout the IGL. Collectively, these results indicated that PACAP acts on granule cell migration as "a brake (stop signal) for cell movement." Furthermore, these results suggest that endogenous PACAP slows granule cell migration when the cells enter the PACAP-rich PCL, and 2 h later the desensitization of PACAP receptors allows the cells to accelerate the rate of migration and to actively move within the PACAP-rich IGL. Therefore, endogenous PACAP may provide a cue that regulates granule cell migration in a cerebellar cortical-layer-specific manner.     

Cell membrane-derived lysophosphatidylcholine activates cardiac ryanodine receptor channels

Lysophosphatidylcholine (LPC) is metabolized from a membrane phospholipid and modulates a variety of channels in the plasma membrane (PM). We examined LPC modulation of cardiac ryanodine receptor (RyR) channels in the sarcoplasmic reticulum (SR) using the planar lipid bilayer method to measure the single-channel currents. Micromolar concentrations of LPC increased the open probability of the reconstituted RyR channels irrespective of whether LPC was added to the cis or trans chamber. LPC also increased the membrane capacitance of the bilayer. The effects of LPC contrasted well with those of sphingosylphosphorylcholine (SPC). Taken together, these results suggest that amphipathic lipid LPC does not bind directly to the RyR channel protein, but rather, is incorporated into the bilayer membrane and activates the channel. Thus, we consider cell membrane-derived LPC to be a putative endogenous mediator that activates not only plasma membrane channels but also RyR channels and induces arrhythmogenic Ca²⁺ mobilization in cardiomyocytes.