Endothelial dysfunction is a critical factor in many cardiovascular diseases, including hypertension. Although lipid signaling has been implicated in endothelial dysfunction and cardiovascular disease, specific molecular mechanisms are poorly understood. Here we report that Nogo-B, a membrane protein of the endoplasmic reticulum, regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, the rate-limiting enzyme of the de novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine 1-phosphate and autocrine, G protein–coupled receptor–dependent signaling by this metabolite. Mice lacking Nogo-B either systemically or specifically in endothelial cells are hypotensive, resistant to angiotensin II–induced hypertension and have preserved endothelial function and nitric oxide release. In mice that lack Nogo-B, pharmacological inhibition of serine palmitoyltransferase with myriocin reinstates endothelial dysfunction and angiotensin II–induced hypertension. Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and shows that autocrine sphingolipid signaling within the endothelium is critical for vascular function and blood pressure homeostasis.

Rationale: Unrepaired cardiomyocyte membrane injury causes irreplaceable cell loss, leading to myocardial fibrosis and eventually heart failure. However, the cellular and molecular mechanisms of cardiac membrane repair are largely unknown. MG53, a newly identified striated muscle-specific protein, is involved in skeletal muscle membrane repair. But the role of MG53 in the heart has not been determined. Objective: We sought to investigate whether MG53 mediates membrane repair in cardiomyocytes and, if so, the cellular and molecular mechanism underlying MG53-mediated membrane repair in cardiomyocytes. Moreover, we determined possible cardioprotective effect of MG53-mediated membrane repair. Methods and Results: We demonstrated that MG53 is crucial to the emergency membrane repair response in cardiomyocytes and protects the heart from stress-induced loss of cardiomyocytes. Disruption of the sarcolemmal membrane by mechanical, electric, chemical, or metabolic insults caused rapid and robust translocation of MG53 toward the injury sites. Ablation of MG53 prevented sarcolemmal resealing after infrared laser-induced membrane damage in intact heart, and exacerbated mitochondrial dysfunction and loss of cardiomyocytes during ischemia/reperfusion injury. Unexpectedly, the MG53-mediated cardiac membrane repair was mediated by a cholesterol-dependent mechanism: depletion of membrane cholesterol abolished, and its recovery restored injury-induced membrane translocation of MG53. The redox status of MG53 did not affect initiation of MG53 translocation, whereas MG53 oxidation conferred stability to the membrane repair patch. Conclusions: Thus, cholesterol-dependent MG53-mediated membrane repair is a vital, heretofore unappreciated cardioprotective mechanism against a multitude of insults and may bear important therapeutic implications. (Circ Res. 2010;107:76-83.)Key Words: membrane repair Ⅲ MG53 Ⅲ cholesterol Ⅲ ischemia/reperfusion injury Ⅲ heart I n eukaryotic cells, the plasma membrane partitions a Ϸ10 000-fold Ca 2ϩ gradient and prevents loss of vital intracellular constituents, thus representing the last line of defense for cell integrity, homeostasis, and function. Physical, chemical or metabolic disruption of the plasma membrane leads to a repairor-die emergency of the cell. Although the natural tendency to reseal the lipid biomembrane acts constitutively, recent studies indicate that plasma membrane disruption requires active emergency response mechanisms to mend the broken membrane. 1 In the heart, plasma membrane repair is of particular importance because cardiomyocytes are terminally differentiated cells, displaying only very limited self-renewal capability. 2 Cardiomyocytes undergo transient membrane injuries that occur as accidents under physiological conditions and can be exacerbated by various pathophysiological stresses. 3 Progressive necrotic and apoptotic cell death causes onset of myocardial fibrosis and undermines cardiac contractile and electrophysiological performance, ultimately leading to heart failure....

Zeolites, microporous aluminosilicate minerals, have high affinity to ammonium in water. This study explored the mechanisms of ammonium adsorption onto natural zeolite and NaCl-modified counterpart under different ammonium levels (10-4000 mg-N/L) and initial pH 3.4-11.1. Ion exchange dominated the ammonium adsorption process near neutral pH, with the order of exchange selectivity following Na + > Ca 2+ > K + > Mg 2+. At high ammonium levels, Ca 2+ exceeded Na + as the dominant ions for ammonium adsorption. Conversely, in strong alkaline solutions, molecular adsorption suppressed ion exchange in ammonium adsorption. NaCl modification effectively increased ammonium adsorption capacity by increasing the Na contents in zeolite and by modifying the surface morphology to enhance film mass transfer rate. The modified zeolite presents a potential adsorbent to reduce ammonium concentration in landfill leachates, livestock wastewaters or effluents from 2 anaerobic digestion tanks of livestock manure.

No abstract

No abstract

We recently discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular function by inhibiting the rate-limiting enzyme, serine palmitoyltransferase (SPT), in de novo sphingolipid biosynthesis. Here, we show that endothelium-derived sphingolipids, particularly sphingosine-1-phosphate (S1P), protect the heart from inflammation, fibrosis, and dysfunction following pressure overload and that Nogo-B regulates this paracrine process. SPT activity is upregulated in banded hearts in vivo as well as in TNF-α–activated endothelium in vitro, and loss of Nogo removes the brake on SPT, increasing local S1P production. Hence, mice lacking Nogo-B, systemically or specifically in the endothelium, are resistant to the onset of pathological cardiac hypertrophy. Furthermore, pharmacological inhibition of SPT with myriocin restores permeability, inflammation, and heart dysfunction in Nogo-A/B–deficient mice to WT levels, whereas SEW2871, an S1P1 receptor agonist, prevents myocardial permeability, inflammation, and dysfunction in WT banded mice. Our study identifies a critical role of endothelial sphingolipid biosynthesis and its regulation by Nogo-B in the development of pathological cardiac hypertrophy and proposes a potential therapeutic target for the attenuation or reversal of this clinical condition.

By fully utilizing the oxidation property of hypochlorites and different coordinating properties of Cu(+) and Cu(2+), the Cu(2+) sensor could act as a new good probe toward hypochlorites with high sensitivity as low as 8.1 × 10(-7) M, providing a novel approach to develop new probes for oxidants.

Sphingolipids are both, fundamental structural components of the eukaryotic membranes and signaling molecules regulating a variety of biological functions. Highly bioactive lipids, ceramide and sphingosine-1-phosphate have emerged as important regulators of cardiovascular functions in health and disease. In this review we discuss recent insights into the role of sphingolipids, particularly ceramide and sphingosine-1-phosphate, in the pathophysiology of the cardiovascular system. We also highlight advances into the molecular mechanisms regulating serine palmitoyltransferase, the first and rate-limiting enzyme of de novo biosynthesis, with an emphasis on recently discovered inhibitors of serine palmitoyltransferase, ORMDL and NOGO-B proteins. Understanding the molecular mechanisms regulating this biosynthetic pathway may lead to the development of novel therapeutic approaches for the treatment of cardiovascular diseases.