Hong-Yan Tian

Serotonin drives the activation of pulmonary artery adventitial fibroblasts and TGF-β1/Smad3-mediated fibrotic responses through 5-HT(2A) receptors.

Pulmonary arterial remodeling is characterized by excessive proliferation, migration, and pro-differentiation and fibrotic activation of adventitial fibroblasts in pulmonary arterial hypertension (PAH) process. Several lines of evidence indicate that serotonin (5-HT) plays a central role in the pathogenesis of pulmonary arterial remodeling. In the present study, we investigated whether 5-HT is directly involved in the functional regulation of pulmonary artery adventitial fibroblasts (PAFs). Incubation of cultured rat PAFs with 5-HT caused a dose-dependent stimulation of cell proliferation, migration activity, and a time-dependent increase of α-SMA expression, a marker of fibroblast differentiation into myofibroblasts, and adventitia fibrosis, evaluating connective tissue growth factor (CTGF) and extracellular matrix (ECM) mRNAs and proteins. These effects were attenuated by the 5-HT2A receptor antagonist, ketanserin and mimicked by the 5-HT2A receptor agonist DOI. 5-HT-induced fibroblasts phenotypic alterations and ECM accumulation were dependent on stimulation of transforming growth factor (TGF)-β1 as demonstrated using a neutralizing antibody. 5-HT also caused Smad3 phosphorylation and ketanserin diminished 5-HT-induced Smad3 activation. These results demonstrated that 5-HT can directly activate PAFs through 5-HT2A receptor and promote fibroblasts phenotypic alterations and adventitia fibrosis depending on the signaling of the TGF-β1/Smad3 pathway.

Serotonin inhibits apoptosis of pulmonary artery smooth muscle cells through 5-HT2A receptors involved in the pulmonary artery remodeling of pulmonary artery hypertension

ABSTRACT Decreased pulmonary artery smooth muscle cell (PASMC) apoptosis play a key role in pulmonary artery remodeling during pulmonary artery hypertension (PAH), but the mechanisms involved are unclear. Serotonin (5-HT) inhibits apoptosis in many pathologic processes by activating the 5-HT2A receptor. Therefore, we hypothesized that 5-HT may be the promoter of decreased apoptosis in PAH through the 5-HT2A receptor. We found that inhibition of the 5-HT2A receptor prevented the increase in pulmonary artery pressure and pulmonary artery remodeling in rats stimulated by monocrotaline. This effect was accompanied by increased apoptosis in the pulmonary artery. Cultured PASMCs stimulated with 5-HT showed a decrease in apoptosis with increased phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), pyruvate dehydrogenase kinase (PDK), and mitochondrial transmembrane potential. These effects were markedly prevented by a 5-HT2A receptor inhibitor, an ERK1/2 activation inhibitor peptide I, or a PDK inhibitor. In conclusion, 5-HT inhibited PASMC apoptosis by activating the 5-HT2A receptor through the pERK1/2 and PDK pathways.5-HT decreasing apoptosis through 5-HT2A receptor is involved, at least in part, in pulmonary artery remolding.

Downregulation of Kir6.1/SUR2B channels in the obese rat aorta.

OBJECTIVE This study was designed to evaluate the contribution of adenosine triphosphate-dependent potassium channels to the increase in blood pressure observed in obese rats. METHODS The experiment was performed in male Sprague-Dawley rats. Glibenclamide-sensitive currents were measured in vascular smooth muscle cells by patch-clamp. Expressions of Kir6.1 and SUR2B were examined by reverse transcription polymerase chain reaction and western blot techniques, respectively. RESULTS In the aortic vascular smooth muscle cells, pinacidil induced glibenclamide-sensitive currents. The current from obese rats was significantly lower (-10.55 +/- 1.63 pA/pF) compared with that from the control rats (-20.18 +/- 2.79 pA/pF). Expressions of Kir6.1 and SUR2B were downregulated in vascular smooth muscle cells of aortas from the obese rats. CONCLUSION These findings suggest that the adenosine triphosphate-dependent potassium channel is downregulated in smooth muscle cells from the aortas of obese rats, which may contribute to the increase in blood pressure in these rats.

High-fat diet may impair KATP channels in vascular smooth muscle cells

K(ATP) channel in vascular smooth muscle cell (VSMC) is closely linked to the etiology of hypertension. The aim of this study was to investigate effect of the high-fat diet-induced obesity on K(ATP) channel and blood pressure. Obesity was induced by a 24-week high-fat diet feeding in rats. Function and expression of K(ATP) channel in mesenteric arteries were examined using myography system, patch clamp and Western blotting. We show that high-fat diet increased blood pressure, decreased K(ATP) channel-mediated relaxation responses and currents, and down-regulated K(ATP) expression in VSMC. In conclusion, diet-induced obesity impairs K(ATP) channels in VSMC, which may underscore obesity-triggered increase in blood pressure.

Effect of PGE2 on DA tone by EP4 modulating Kv channels with different oxygen tension between preterm and term

OBJECTIVE To investigate common downstream mechanism of PGE2 and O2-sensitive voltage-dependent potassium (Kv) channels in preterm and term DA tone regulations, for suggesting respective prescriptions for preterm and term PDA. STUDY DESIGN The expressions of Kv1.2, 1.5 and 2.1 were compared between preterm and term in rabbit and human DAs at mRNA and protein levels; DA contracting responses caused by O2, Kv channels blocker 4-AP, EP4 antagonist GW627368X, and PGE2 reduce using vessels rings and Whole-Cell Patch-Clamp were explored. RESULTS Kv 1.2 and 2.1 expressions were developed with pregnant age in preterm DA and decreased after birth with oxygen stimulation in term DA. GW627368X led significant DA constriction and DASMC IK current decrease in preterm, which was slimier to 4-AP effects, but just slightly influenced on DA tension and DASMC IK current at term. In addition, PGE2 led great DA dilation and IK current increase of DASMC in preterm but not in term. These DA tension and IK current changes were in line with Kv channel expressions. CONCLUSION Higher levels of PGE2 binds with GPCR EP4, which activates G-protein to couple with O2-sensitive Kv channels and to open them, leading to DA vasorelaxation in the fetus. It indicates that EP4 inhibitors, instead of PGE2 or its analogue PGE1, may be a selectable strategy for preterm PDA.

Altered ATP-sensitive potassium channels may underscore obesity-triggered increase in blood pressure.

AbstractAim:To determine whether ATP-sensitive potassium channels are altered in VSMC from arotas and mesenteric arteries of obese rat, and their association with obesity-triggered increase in blood pressure.Methods:Obesity was induced by 24 weeks of high-fat diet feeding in male Sprague-Dawley rats. Control rats were fed with standard laboratory rat chow. Blood pressure and body weight of these rats were measured every 4 weeks. At the end of 24 weeks, KATP channel-mediated relaxation responses in the aortas and mesenteric arteries, KATP channel current, and gene expression were examined, respectively.Results:Blood pressure and body weight were increased in rats fed with high-fat diet. KATP channel-mediated relaxation responses, currents, and KATP expression in VSMC of both aortas and mesenteric arteries were inhibited in these rats.Conclusion:Altered ATP-sensitive potassium channels in obese rats may underscore obesity-triggered increase in blood pressure.

Oleic Acid Inhibits the KATP Channel Subunit Kir6.1 and the KATP Current in Human Umbilical Artery Smooth Muscle Cells

Background:The objective of the present study was to determine the effect of various concentrations of oleic acid (OA) on KATP channel expression and the potential relationship to exogenous nitrogen monoxide and protein kinase C levels. Methods:Human umbilical artery smooth muscle cells (HUASMCs), between the 7th and 10th passages, were divided into control group, OA group (final OA concentration of 0, 50, 100 or 200 &mgr;mol/L), nitric oxide (NO) intervention group, protein kinase C inhibitor group or GF-109203X (GFX) intervention group. Western immunoblotting was used to detect the protein expression of the KATP channel subunit Kir6.1. Also, quantitative real-time polymerase chain reaction analysis to determine Kir6.1 messenger RNA levels and whole-cell patch clamping to measure KATP currents were performed. Results:The results suggested that OA inhibited Kir6.1 protein and messenger RNA expression in HUASMCs. Under a high concentration of potassium (140 mmol/L), 100 &mgr;mol/L OA significantly reduced ATP-sensitive potassium current density, whereas a low extracellular concentration of potassium (5.4 mmol/L) did not influence KATP density. Pretreatment with either exogenous NO or GFX weakened the OA-induced inhibition of KATP in HUASMCs. Conclusions:The study demonstrated that OA inhibited Kir6.1, a KATP channel subunit, in HUASMCs, and indirectly inhibited the KATP current. In addition, the results indicated that NO and/or GFX partially reversed OA inhibition in HUASMCs.

Resistin may be an independent predictor of subclinical atherosclerosis formale smokers

Abstract To investigate whether resistin is associated with early atherosclerosis in male smokers. The present study consecutively enrolled 50 male smokers. Their serum resistin contents were detected with enzyme linked immunosorbent assay (ELISA), and subclinical atherosclerosis indices, including carotid inner middle thickness (IMT) and arterial elasticity indices (C1 and C2), were measured. The association between serum resistin levels and IMT, C1 and C2 were respectively evaluated with the Pearson’s correlation coefficient method. The results showed that the serum resistin level had a positive association with IMT (r = 0.307, p = .030), but were both inversely associated with C1 (r = −0.440, p = .001) and C2 (r = −0.381, p = .006). These associations remained significant even after adjustment for cardiovascular confounders. In conclusion, serum resistin concentration was independently associated with early atherosclerosis in male smokers.

The effects of the 5-HT2A receptor antagonist sarpogrelate hydrochloride on chronic hypoxic pulmonary hypertension in rats

ABSTRACT Purpose of the Study: This study investigated whether sarpogrelate hydrochloride (SPG), a 5-HT2A receptor antagonist, alleviates chronic hypoxic pulmonary hypertension (CH-PH) in rats by stimulating apoptosis and inhibiting proliferation in pulmonary artery smooth muscle cells (PASMCs). Materials and Methods: Forty male Sprague-Dawley rats were pretreated with SPG (50 mg/kg/day by oral gavage) or saline vehicle and then subjected to chronic hypoxia (CH) (hypobaric chamber set to 380 mmHg, 10% oxygen) or normoxia for 14 days. Mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (RVH) were measured. Hypertensive pulmonary vascular remodeling was assayed by light microscopy. Terminal deoxynucletidyl transferase dUTP nick end ligase (TUNEL) assays, western blotting, and real-time polymerase chain reaction were used to assess apoptosis, proliferation and underlying signaling pathways in PASMCs from lung tissue and isolated pulmonary artery rings. Results: CH increased mean PAP and RVH. CH increased the percentage of muscularized arteries in the peripheral pulmonary vasculature and medial wall thickness in small muscular arteries. CH increased pulmonary protein and mRNA levels of the B-cell lymphoma protein 2 (Bcl-2), pyruvate dehydrogenase kinase (PDK), phosphorylation of extracellular signal-regulated kinases 1 and 2 (pERK1/2), cyclin D1, proliferating cell nuclear antigen (PCNA) and decreased protein and mRNA levels of Bcl-2-associated X protein (BAX), cleaved caspase-3. Pretreatment with SPG, which has been shown previously to inhibit ERK1/2 phosphorylation and PDK, countered all of these effects. Isolated pulmonary artery rings incubated with 5-HT increased pERK1/2, PDK, and Bcl-2 expression, and decreased Bax expression. Conclusion: Administration of SPG ameliorated the development of CH-PH by stimulating apoptosis in and inhibiting proliferation of PASMCs.

Paradoxical embolism: A report of 2 cases

Rationale: Paradoxical embolism (PDE) refers to direct passage of venous thrombi into the arterial circulation through an arteriovenous shunt. Patient concerns: Case 1 presented with initial symptoms of shock and cerebral infarction. Case 2 developed middle cerebral artery occlusion during angiography. Diagnoses: 2 cases were diagnosed as PDE. Interventions: They received thrombolytic therapy and anticoagulant therapy. Outcomes: The patients had recovery. Lessons: This report highlights the myriad clinical manifestations of PDE and underlines the importance of meticulous history taking and physical examination for early diagnosis.