sphingosine-kinase and Hypertension

Isoflurane preconditioning could reduce different kinds of brain injury via sphingosine kinase (SPK). Both sphingosine kinase 1 and sphingosine kinase 2 play important roles in brain protection. However, the effects of isoflurane preconditioning on SPK expression in hypertension have not been investigated before.. To verify whether the neuroprotective effects of the anesthetic isoflurane after an ischemic injury are altered in hypertension and to identify its possible mechanisms involving SPK.. Wistar rats (control) and spontaneous hypertension rats (SHR) were exposed to isoflurane preconditioning before transient middle cerebral artery occlusion. The infarct volumes of cortical and subcortical brain areas were measured. The expression levels of SPK1 and SPK2 were measured before and after isoflurane preconditioning.. In the SHR group, isoflurane preconditioning significantly reduced only the infarct volumes of the subcortical brain (p < 0.05), not of the cortical brain. After 3 h of isoflurane exposure and preconditioning, SPK2 levels in the SHR group increased in the cortical brain (p < 0.05), but not in the subcortical brain area, Unlike in the control group, isoflurane exposure and preconditioning could significantly increase SPK2 levels in both cortical and subcortical brain area.. The brain protection effects induced by isoflurane preconditioning after an ischemic injury are mainly mediated by the SPK2 isoform and are somewhat impaired in hypertension. Attention should be paid to ischemic injury patients with hypertension.

Topics: Anesthetics, Inhalation; Animals; Brain Ischemia; Humans; Hypertension; Ischemic Preconditioning; Isoflurane; Phosphotransferases (Alcohol Group Acceptor); Rats; Rats, Wistar; Sphingosine

Hypertension is considered the major modifiable risk factor for the development of cognitive impairment. Because increased blood pressure is often accompanied by an activation of the immune system, the concept of neuro-inflammation gained increasing attention in the field of hypertension-associated neurodegeneration. Particularly, hypertension-associated elevated circulating T-lymphocyte populations and target organ damage spurred the interest to understanding mechanisms leading to inflammation-associated brain damage during hypertension. The present study describes sphingosine-1-phosphate (S1P) as major contributor to T-cell chemotaxis to the brain during hypertension-associated neuro-inflammation and cognitive impairment. Using Western blotting, flow cytometry and mass spectrometry approaches, we show that hypertension stimulates a sphingosine kinase 1 (SphK1)-dependent increase of cerebral S1P concentrations in a mouse model of angiotensin II (AngII)-induced hypertension. The development of a distinct S1P gradient between circulating blood and brain tissue associates to elevated CD3+ T-cell numbers in the brain. Inhibition of S1P₁-guided T-cell chemotaxis with the S1P receptor modulator FTY720 protects from augmentation of brain CD3 expression and the development of memory deficits in hypertensive WT mice. In conclusion, our data highlight a new approach to the understanding of hypertension-associated inflammation in degenerative processes of the brain during disease progression.

Topics: Angiotensin II; Animals; Brain; Chemokines; Chemotaxis; Cognition Disorders; Female; Hypertension; Lysophospholipids; Male; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Phosphotransferases (Alcohol Group Acceptor); Sphingosine; T-Lymphocytes

Undernutrition during childhood leads to chronic diseases in adult life including hypertension, diabetes and chronic kidney disease. Here we explore the hypothesis that physiological alterations in the bioactive lipids pattern within kidney tissue might be involved in the progression of chronic kidney disease.. Membrane fractions from kidney homogenates of undernourished rats (RBD) were submitted to lipid extraction and analysis by thin layer chromatography and cholesterol determination.. Kidneys from RBD rats had 25% lower cholesterol content, which disturb membrane microdomains, affecting Ca. Results point to an imbalance in the bioactive lipid generation with further consequences to key events related to kidney function, thus contributing to the establishment of chronic kidney disease.

Topics: 1-Phosphatidylinositol 4-Kinase; Animals; Animals, Newborn; Ceramides; Cholesterol; Diacylglycerol Kinase; Gene Expression Regulation; Hypertension; Kidney; Lipid Metabolism; Male; Malnutrition; Membrane Microdomains; Phosphatidic Acids; Phosphatidylinositol Phosphates; Phospholipases A2; Phosphotransferases (Alcohol Group Acceptor); Rats; Rats, Wistar; Renal Insufficiency, Chronic

Vascular dysfunction is an important phenomenon in hypertension. We hypothesized that angiotensin II (AngII) affects transcriptome in the vasculature in a region-specific manner, which may help to identify genes related to vascular dysfunction in AngII-induced hypertension. Mesenteric artery and aortic transcriptome was profiled using Illumina WG-6v2.0 chip in control and AngII infused (490 ng/kg/min) hypertensive mice. Gene set enrichment and leading edge analyses identified Sphingosine kinase 1 (Sphk1) in the highest number of pathways affected by AngII. Sphk1 mRNA, protein and activity were up-regulated in the hypertensive vasculature. Chronic sphingosine-1-phosphate (S1P) infusion resulted in a development of significantly increased vasoconstriction and endothelial dysfunction. AngII-induced hypertension was blunted in Sphk1

Topics: Angiotensin II; Animals; Aortic Dissection; Gene Expression Profiling; Hypertension; Male; Mice; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor)

Angiotensin II (AngII) plays a critical role in the regulation of vascular tone and blood pressure mainly via regulation of Ca(2+) mobilization. Several reports have implicated sphingosine kinase 1 (SK1)/sphingosine 1-phosphate (S1P) in the mobilization of intracellular Ca(2+) through a yet-undefined mechanism. Here we demonstrate that AngII-induces biphasic calcium entry in vascular smooth muscle cells, consisting of an immediate peak due to inositol tris-phosphate-dependent release of intracellular calcium, followed by a sustained transmembrane Ca(2+) influx through store-operated calcium channels (SOCs). Inhibition of SK1 attenuates the second phase of transmembrane Ca(2+) influx, suggesting a role for SK1 in AngII-dependent activation of SOC. Intracellular S1P triggers SOC-dependent Ca(2+) influx independent of S1P receptors, whereas external application of S1P stimulated S1P receptor-dependent Ca(2+) influx that is insensitive to inhibitors of SOCs, suggesting that the SK1/S1P axis regulates store-operated calcium entry via intracellular rather than extracellular actions. Genetic deletion of SK1 significantly inhibits both the acute hypertensive response to AngII in anaesthetized SK1 knockout mice and the sustained hypertensive response to continuous infusion of AngII in conscious animals. Collectively these data implicate SK1 as the missing link that connects the angiotensin AT1A receptor to transmembrane Ca(2+) influx and identify SOCs as a potential intracellular target for SK1.

Topics: Angiotensin II; Animals; Blood Pressure; Calcium; Calcium Channels; Cell Membrane; Chronic Disease; Enzyme Activation; Gene Deletion; HEK293 Cells; Humans; Hypertension; Lysophospholipids; Male; Mice, Inbred C57BL; Phosphotransferases (Alcohol Group Acceptor); Rats, Sprague-Dawley; Receptors, Lysosphingolipid; Sphingosine

Accumulating evidence suggests that sphingosine kinase 1 (SphK1) plays a key role in carcinogenesis by regulating cyclooxygenase-2 (COX-2) expression. Recent clinical studies have revealed that COX-2 inhibitors cause adverse cardiovascular side effects, likely due to inhibition of prostacyclin (PGI(2)). In this work, we investigated the roles of SphK1 inhibition on blood pressure (BP). The results show that lack of SphK1 expression did not exacerbate angiotensin II (Ang II)-induced acute hypertension, whereas celecoxib, a COX-2 inhibitor, augmented and sustained higher BP in mice. Interestingly, SphK1-knockout mice inhibited prostaglandin E(2) (PGE(2)) but not PGI(2) production in response to Ang II, whereas celecoxib blocked both PGE(2) and PGI(2) production. Mechanistically, SphK1 down-regulation by siRNA in human umbilical vein endothelial cells decreased cytokine-induced PGE(2) production primarily through inhibition of microsomal PGE synthase-1 (mPGES-1), not COX-2. SphK1 down-regulation also decreased MKK6 expression, which phosphorylates and activates P38 MAPK, which, in turn, regulates early growth response-1 (Egr-1), a transcription factor of mPGES-1. Together, these data indicate that SphK1 regulates PGE(2) production by mPGES-1 expression via the p38 MAPK pathway, independent of COX-2 signaling, in endothelial cells, suggesting that SphK1 inhibition may be a promising strategy for cancer chemoprevention with lack of the adverse cardiovascular side effects associated with coxibs.

Topics: Animals; Base Sequence; Blood Pressure; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Epoprostenol; Gene Knockdown Techniques; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Intramolecular Oxidoreductases; Male; MAP Kinase Signaling System; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mitochondrial Proteins; Phosphotransferases (Alcohol Group Acceptor); Prostaglandin-E Synthases; Pyrazoles; RNA, Small Interfering; Sulfonamides

FTY720 (Fingolimod) is a recently approved orally administered drug for the treatment of multiple sclerosis. Phase II and III clinical trials have demonstrated that this drug modestly increases BP. We previously showed that inhibition of sphingosine kinase increases vascular tone and BP in hypertensive, but not normotensive rats. Since FTY720 is reported to have inhibitory effects on sphingosine kinase, we investigated whether FTY720 increases vascular tone and BP only in hypertensive rats via this mechanism.. The contractile and BP modulating effects of FTY720 were studied in vivo and ex vivo (wire myography) in age-matched normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs).. Oral administration of FTY720 induced an increase in mean arterial pressure in SHR, whereas a decrease in BP was observed in WKY rats, as measured 24 h after administration. Similar to the sphingosine kinase inhibitor dimethylsphingosine (DMS), FTY720 induced large contractions in isolated carotid arteries from SHR, but not in those from WKY. In contrast, the phosphorylated form of FTY720 did not induce contractions in isolated carotid arteries from SHR. FTY720-induced contractions were inhibited by endothelium denudation, COX and thromboxane synthase inhibitors, and by thromboxane receptor antagonism, indicating that (like DMS-induced contractions) they were endothelium-dependent and mediated by thromboxane A₂.. These data demonstrate that FTY720 increases vascular tone and BP only in hypertensive rats, most likely as a result of its inhibitory effect on sphingosine kinase.

Topics: Animals; Blood Pressure; Carotid Arteries; Cyclooxygenase Inhibitors; Endothelium, Vascular; Enzyme Inhibitors; Fingolimod Hydrochloride; Hypertension; Immunosuppressive Agents; Isoenzymes; Male; Muscle, Smooth, Vascular; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Propylene Glycols; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sphingosine; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents