Medicine and Health Sciences Commons^™

Antihypertensive Treatment Differentially Affects Vascular Sphingolipid Biology In Spontaneously Hypertensive Rats, Léon J. A. Spijkers, Ben J. A. Janssen, Jelly Nelissen, Merlijn J. P. M. T. Meens, Dayanjan Wijesinghe, Charles E. Chalfant, Jo G. R. De Mey, Astrid E. Alewijnse, Stephan L. M. Peters

Biochemistry and Molecular Biology Publications

We have previously shown that essential hypertension in humans and spontaneously hypertensive rats (SHR), is associated with increased levels of ceramide and marked alterations in sphingolipid biology. Pharmacological elevation of ceramide in isolated carotid arteries of SHR leads to vasoconstriction via a calcium-independent phospholipase A2, cyclooxygenase-1 and thromboxane synthase-dependent release of thromboxane A2. This phenomenon is almost absent in vessels from normotensive Wistar Kyoto (WKY) rats. Here we investigated whether lowering of blood pressure can reverse elevated ceramide levels and reduce ceramide-mediated contractions in SHR.

Methods and Findings

For this purpose SHR were treated for 4 weeks with the angiotensin …

Spag16, An Axonemal Central Apparatus Gene, Encodes A Male Germ Cell Nuclear Speckle Protein That Regulates Spag16 Mrna Expression, David R. Nagarkatti-Gude, Ruth Jaimez, Scott C. Henderson, Maria E. Teves, Zhibing Zhang, Jerome F. Strauss Iii

Biochemistry and Molecular Biology Publications

Spag16 is the murine orthologue of Chlamydomonas reinhardtii PF20, a protein known to be essential to the structure and function of the “9+2” axoneme. In Chlamydomonas, the PF20gene encodes a single protein present in the central pair of the axoneme. Loss of PF20 prevents central pair assembly/integrity and results in flagellar paralysis. Here we demonstrate that the murine Spag16 gene encodes two proteins: 71 kDa SPAG16L, which is found in all murine cells with motile cilia or flagella, and 35 kDa SPAG16S, representing the C terminus of SPAG16L, which is expressed only in male germ cells, and is …

Crystal Structure Of Thrombin In Complex With S-Variegin: Insights Of A Novel Mechanism Of Inhibition And Design Of Tunable Thrombin Inhibitors, Cho Yeow Koh, Sundramurthy Kumar, Maria Kazimirova, Patricia A. Nuttall, Uvaraj P. Radhakrishnan, Seongcheol Kim, Pudur Jagadeeswaran, Takayuki Imamura, Jun Mizuguchi, Sadaaki Iwanaga, Kunchithapadam Swaminathan, R. Manjunathan Kini

Biochemistry and Molecular Biology Publications

The inhibition of thrombin is one of the important treatments of pathological blood clot formation. Variegin, isolated from the tropical bont tick, is a novel molecule exhibiting a unique ‘two-modes’ inhibitory property on thrombin active site (competitive before cleavage, noncompetitive after cleavage). For the better understanding of its function, we have determined the crystal structure of the human α-thrombin:synthetic-variegin complex at 2.4 Å resolution. The structure reveals a new mechanism of thrombin inhibition by disrupting the charge relay system. Based on the structure, we have designed 17 variegin variants, differing in potency, kinetics and mechanism of inhibition. The most active …

Hypertension Is Associated With Marked Alterations In Sphingolipid Biology: A Potential Role For Ceramide, Leon J. A. Spijkers, Rob F. P. Van Den Akker, Ben J. A. Janssen, Jacques J. Debets, Jo G. R. De Mey, Erik S. G. Stroes, Bart-Jan H. Van Den Bom, Dayanjan Wijesinghe, Charles E. Chalfant, Luke Macaleese, Gert B. Eijkel, Ron M. A. Heeren, Astrid E. Alewijnse, Stephan L. M. Peters

Biochemistry and Molecular Biology Publications

Background

Hypertension is, amongst others, characterized by endothelial dysfunction and vascular remodeling. As sphingolipids have been implicated in both the regulation of vascular contractility and growth, we investigated whether sphingolipid biology is altered in hypertension and whether this is reflected in altered vascular function.

Methods and Findings

In isolated carotid arteries from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, shifting the ceramide/S1P ratio towards ceramide dominance by administration of a sphingosine kinase inhibitor (dimethylsphingosine) or exogenous application of sphingomyelinase, induced marked endothelium-dependent contractions in SHR vessels (DMS: 1.4±0.4 and SMase: 2.1±0.1 mN/mm; n = 10), that were virtually …