Rosiglitazone Restores Endothelial Dysfunction in a Rat Model of Metabolic Syndrome through PPARγ- and PPARδ-Dependent Phosphorylation of Akt and eNOS

Vascular endothelial dysfunction has been demonstrated in metabolic syndrome (MS). Chronic administration of rosiglitazone ameliorates endothelial dysfunction through PPARγ-mediated metabolic improvements. Recently, studies suggested that single dose of rosiglitazone also has direct vascular effects, but the mechanisms remain uncertain. Here we established a diet-induced rat model of MS. The impaired vasorelaxation in MS rats was improved by incubating arteries with rosiglitazone for one hour. Importantly, this effect was blocked by either inhibition of PPARγ or PPARδ. In cultured endothelial cells, acute treatment with rosiglitazone increased the phosphorylation of Akt and eNOS and the production of NO. These effects were also abolished by inhibition of PPARγ, PPARδ, or PI3K. In conclusion, rosiglitazone improved endothelial function through both PPARγ- and PPARδ-mediated phosphorylation of Akt and eNOS, which might help to reconsider the complex effects and clinical applications of rosiglitazone

Human umbilical cord mesenchymal stem cells inhibit coronary artery injury in mice with Lactobacillus casei wall extract-induced kawasaki disease

Kawasaki disease (KD) is a serious threat to children’s physical and mental health. This study investigated the effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) on KD coronary arteritis induced by Lactobacillus casei wall extract (LCWE) in an animal model. Sixty BALB/C mice were randomly assigned to three groups (n = 20 mice per group). Mice in the model and stem-cell groups were injected with LCWE, while the control-group mice were injected with phosphate-buffered saline (PBS) for 2 days. At day 16 of modeling, PBS was injected into the control and model-group mice, and hUC-MSCs were injected into the stem-cell group mice for 10 days. At days 4, 15, 26, and 32 of modeling, echocardiography and histopathology were performed to examine the cardiac structure and the morphological changes in the coronary arteries in each group. B-ultrasonography showed that 57.5% (23/40) of the mice had coronary artery lesions, of which 5% (2/40) had right coronary artery aneurysm, 27.5% (11/40) had coronary artery wall thickening, a widened inner diameter of the main artery of the left coronary artery, and thickened intima. Histopathology showed slight swelling of the epicardium of the aortic valve, mitral valve, right ventricle, and atrium, as well as scattered infiltration of a few neutrophils. Following hUC-MSCs intervention treatment, B-ultrasonography showed a decrease in the main coronary artery diameter, while histopathology showed no obvious vascular inflammatory reaction or other obvious abnormalities. These findings highlight that hUC-MSCs inhibit coronary artery injury in animal models of KD induced by LCWE

Caffeine intake antagonizes salt sensitive hypertension through improvement of renal sodium handling

High salt intake is a major risk factor for hypertension. Although acute caffeine intake produces moderate diuresis and natriuresis, caffeine increases the blood pressure (BP) through activating sympathetic activity. However, the long-term effects of caffeine on urinary sodium excretion and blood pressure are rarely investigated. Here, we investigated whether chronic caffeine administration antagonizes salt sensitive hypertension by promoting urinary sodium excretion. Dahl salt-sensitive (Dahl-S) rats were fed with high salt diet with or without 0.1% caffeine in drinking water for 15 days. The BP, heart rate and locomotor activity of rats was analyzed and urinary sodium excretion was determined. The renal epithelial Na+ channel (ENaC) expression and function were measured by in vivo and in vitro experiments. Chronic consumption of caffeine attenuates hypertension induced by high salt without affecting sympathetic nerve activity in Dahl-S rats. The renal α-ENaC expression and ENaC activity of rats decreased after chronic caffeine administration. Caffeine increased phosphorylation of AMPK and decrease α-ENaC expression in cortical collecting duct cells. Inhibiting AMPK abolished the effect of caffeine on α-ENaC. Chronic caffeine intake prevented the development of salt-sensitive hypertension through promoting urinary sodium excretion, which was associated with activation of renal AMPK and inhibition of renal tubular ENaC

TRPV1 Activation Attenuates High-Salt Diet-Induced Cardiac Hypertrophy and Fibrosis through PPAR- δ

High-salt diet-induced cardiac hypertrophy and fibrosis are associated with increased reactive oxygen species production. Transient receptor potential vanilloid type 1 (TRPV1), a specific receptor for capsaicin, exerts a protective role in cardiac remodeling that resulted from myocardial infarction, and peroxisome proliferation-activated receptors δ (PPAR-δ) play an important role in metabolic myocardium remodeling. However, it remains unknown whether activation of TRPV1 could alleviate cardiac hypertrophy and fibrosis and the effect of cross-talk between TRPV1 and PPAR-δ on suppressing high-salt diet-generated oxidative stress. In this study, high-salt diet-induced cardiac hypertrophy and fibrosis are characterized by significant enhancement of HW/BW%, LVEDD, and LVESD, decreased FS and EF, and increased collagen deposition. These alterations were associated with downregulation of PPAR-δ, UCP2 expression, upregulation of iNOS production, and increased oxidative/nitrotyrosine stress. These adverse effects of long-term high-salt diet were attenuated by chronic treatment with capsaicin. However, this effect of capsaicin was absent in TRPV1−/− mice on a high-salt diet. Our finding suggests that chronic dietary capsaicin consumption attenuates long-term high-salt diet-induced cardiac hypertrophy and fibrosis. This benefit effect is likely to be caused by TRPV1 mediated upregulation of PPAR-δ expression

Increased Migration of Monocytes in Essential Hypertension Is Associated with Increased Transient Receptor Potential Channel Canonical Type 3 Channels

Increased transient receptor potential canonical type 3 (TRPC3) channels have been observed in patients with essential hypertension. In the present study we tested the hypothesis that increased monocyte migration is associated with increased TRPC3 expression. Monocyte migration assay was performed in a microchemotaxis chamber using chemoattractants formylated peptide Met-Leu-Phe (fMLP) and tumor necrosis factor-α (TNF-α). Proteins were identified by immunoblotting and quantitative in-cell Western assay. The effects of TRP channel-inhibitor 2–aminoethoxydiphenylborane (2-APB) and small interfering RNA knockdown of TRPC3 were investigated. We observed an increased fMLP-induced migration of monocytes from hypertensive patients compared with normotensive control subjects (246±14% vs 151±10%). The TNF-α-induced migration of monocytes in patients with essential hypertension was also significantly increased compared to normotensive control subjects (221±20% vs 138±18%). In the presence of 2-APB or after siRNA knockdown of TRPC3 the fMLP-induced monocyte migration was significantly blocked. The fMLP-induced changes of cytosolic calcium were significantly increased in monocytes from hypertensive patients compared to normotensive control subjects. The fMLP-induced monocyte migration was significantly reduced in the presence of inhibitors of tyrosine kinase and phosphoinositide 3-kinase. We conclude that increased monocyte migration in patients with essential hypertension is associated with increased TRPC3 channels

Activation of TRPV1 by Dietary Capsaicin Improves Endothelium-Dependent Vasorelaxation and Prevents Hypertension

Some plant-based diets lower the cardiometabolic risks and prevalence of hypertension. New evidence implies a role for the transient receptor potential vanilloid 1 (TRPV1) cation channel in the pathogenesis of cardiometabolic diseases. Little is known about impact of chronic TRPV1 activation on the regulation of vascular function and blood pressure. Here we report that chronic TRPV1 activation by dietary capsaicin increases the phosphorylation of protein kinase A (PKA) and eNOS and thus production of nitric oxide (NO) in endothelial cells, which is calcium dependent. TRPV1 activation by capsaicin enhances endothelium-dependent relaxation in wild-type mice, an effect absent in TRPV1-deficient mice. Long-term stimulation of TRPV1 can activate PKA, which contributes to increased eNOS phosphorylation, improves vasorelaxation, and lowers blood pressure in genetically hypertensive rats. We conclude that TRPV1 activation by dietary capsaicin improves endothelial function. TRPV1-mediated increase in NO production may represent a promising target for therapeutic intervention of hypertension

Expression and function of transient receptor potential channel TRPC3 and TRPC5 in primary hypertension

GesamtdissertationCanonical Transient Receptor Potential (TRPC) Kanäle sind nicht-selektive Kationen-Kanäle und in viele Signaltransduktionsprozesse eingeschaltet. Die Bedeutung von TRPC Kanälen bei der essentiellen Hypertonie ist bislang noch nicht untersucht worden. TRPC-Kanäle wurden bei 51 Patienten mit essentieller Hypertonie und 51 altersgleichen normotensiven Kontrollpersonen untersucht. Die Expression von TRPC-Kanälen wurde mit Reverser-Transkriptase-Polymerase- Kettenreaktion (RT-PCR), mit Immunoblotting und mit quantitativem in-cell Western Assay bestimmt. Gen-silencing erfolgte mit spezifischer small- interfering RNA (siRNA). Der Calcium- und der Gadolinium-Einstrom in Monozyten wurden mittels Fluoreszenz-Spektrophotometrie bestimmt. In humanen Monozyten wurden die Transkripte für TRPC3 und TRPC5 mittels RT-PCR nachgewiesen. TRPC3- und TRPC5-Kanal-Proteine wurden in Monozyten mittels Immunoblots nachgewiesen. Es zeigte sich eine gesteigerte Expression von TRPC3 und TRPC5 bei Patienten mit essentieller Hypertonie im Vergleich mit normotensiven Kontrollpersonen (normalisierte TRPC3 Expression: 3,21 ± 0,59 versus 1,36 ± 0,07 jeweils n = 20; p < 0,01; normalisierte TRPC5 Expression: 2,10 ± 0,28 versus 1,40 ± 0,52; jeweils n = 12; p < 0,05). Bei Monozyten von Patienten mit essentieller Hypertonie ergab sich ein signifikant gesteigerter Kationen-Einstrom im Vergleich mit normotensiven Kontrollpersonen (Gadolinium/Calcium-Einstrom, 125 ± 14% versus 80 ± 7%; jeweils n = 51; p < 0,01). Nach dem Einsatz von small interfering RNA gegen TRPC5 kam es zu einer signifikanten Verminderung der TRPC5-Kanal-Expression und zur Verminderung des Calcium- und des Gadolinium- Einstroms. Weiterhin zeigte sich auch eine gesteigerte Expression von TRPC3 sowie ein gesteigerter Calcium-Einstrom in Monozyten von spontanhypertensiven Ratten im Vergleich mit normotensiven Wistar-Kyoto-Ratten. Diese Ergebnisse weisen auf eine wesentliche Bedeutung von TRPC-Kanälen in der Pathogenese der essentiellen Hypertonie hin.Canonical transient receptor potential (TRPC) channels are nonselective cation channels which are involved in cellular signal transduction. The role of TRPC channels has not yet been investigated in the pathogenesis of essential hypertension. We studied TRPC channels in 51 patients with essential hypertension and 51 age-matched and sex-matched normotensive control subjects. The expression of TRPC was measured using reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting, and quantitative in-cell western assay. Gene silencing by small interfering RNA for specific TRPC knockdown was also performed. The influx of calcium and gadolinium into monocytes was determined using the fluorescent dye technique. TRPC3 and TRPC5 mRNA was detected in human monocytes using RT-PCR. The expression of TRPC3- and TRPC5-channel protein in human monocytes was confirmed using immunoblotting. We observed a significant increase of TRPC3 and TRPC5 protein expression in essential hypertensive patients compared with normotensive control subjects (normalized TRPC3 expression, 3.21 ± 0.59 versus 1.36 ± 0.07; each n = 20; p < 0.01; normalized TRPC5 expression, 2.10 ± 0.28 versus 1.40 ± 0.52; each n = 12; p < 0.05). We observed an increased gadolinium/calcium-influx ratio in essential hypertensive patients compared with normotensive control subjects (gadolinium/calcium influx ratio, 125 ± 14% versus 80 ± 7%; each n = 51; p < 0.01). Knockdown of TRPC5 using small interfering RNA reduced channel expression and caused a significant attenuation of calcium and gadolinium influx. The calcium-influx was significantly increased in monocytes from spontaneously hypertensive rats compared to normotensive Wistar-Kyoto-rats. This study points to an important role of TRPC channels in essential hypertension

The Gastrointestinal Tract: an Initial Organ of Metabolic Hypertension?

Hypertension is an important global public-health challenge because of its high prevalence and concomitant risks for cardiovascular and kidney diseases. More than 60% of the risk factors for hypertension are associated with metabolic disorders. Furthermore, many metabolic risk factors can directly cause the vascular dysfunction and the elevated blood pressure. Metabolic disorders not only increase the risk for hypertension but also participate in the development of hypertension. Thus, some types of hypertension induced by metabolic disturbances can be defined as metabolic hypertension. However, the pathogenesis of metabolic hypertension remains largely unknown. The gastrointestinal tract is a unique gate through which external food, metabolites, and microbes enter the human body. Thus, metabolism-related risk factors may affect blood pressure through the gastrointestinal tract and alter processes such as taste perception, mucosal absorption, gut hormone homeostasis, GI nerve activity, and gut microbiota. Meanwhile, gastrointestinal intervention through dietary approaches, gut microbiota modification, and metabolic surgery could profoundly improve or remit the vascular dysfunction and metabolic hypertension. It suggests that the GI tract could be an initial organ of metabolic hypertension. However, more clinical and basic studies are necessary to further validate this novel concept