Trained immunity: A link between risk factors and cardiovascular disease.

Cardiovascular diseases are significant contributors to human mortality, closely associated with inflammation. With the changing living conditions and the extension of human lifespan, greater attention has been directed towards understanding the impact of early, long-term events on the development of cardiovascular events. Lifestyle factors such as stress, unhealthy diet and physical inactivity can increase the risk of cardiovascular diseases. Interestingly, even if the risk factors are addressed later, their influence may persist. Recently, the concept of trained innate immunity (TRIM), defined as sustained alterations in the function of innate immunocyte that promote a more robust response to downstream stimuli, has been proposed to be involved in cardiovascular diseases. It is hypothesized that TRIM may serve as a mediator bridging the impacts of aforementioned risk factors. This review aims to elucidate the role of TRIM in cardiovascular diseases and highlight its significance in uncovering new mechanisms and therapeutic targets.

An asymptomatic perforation of the gastrointestinal tract caused by ingestion of foreign body: A case report.

Ingestion of foreign bodies is very common in clinical practice. However, gastrointestinal perforation caused by a foreign body is rare, as most foreign bodies can pass the alimentary tract spontaneously or be removed endoscopically. Ingesting a foreign body causes gastrointestinal tract perforation in less than 1% of cases that require surgery. In the past, the literature about gastrointestinal tract perforation caused by foreign bodies had been widely reported worldwide. However, the case of foreign bodies causing gastrointestinal perforation without significant abdominal infection was rarely documented. A 47-year-old woman presented with intermittent left lower abdominal pain associated with a mass for 1 month and had no other symptoms. Laparotomy was performed after clinical assessment. During the operation, a local inflammatory mass that adhered to the abdominal wall, part of the small intestine, and sigmoid colon was found in the left lower quarter of the abdominal cavity. The surrounding intestinal wall was edematous. There were two bony foreign bodies in it. Postoperative pathology suggested an inflammatory mass. A foreign body rarely migrates into the abdominal cavity without symptoms that may be related to the omentum's slow perforation process and good function. The best treatment is surgery and using appropriate antibiotics.

Engineering inducible biomolecular assemblies for genome imaging and manipulation in living cells.

Genome architecture and organization play critical roles in cell life. However, it remains largely unknown how genomic loci are dynamically coordinated to regulate gene expression and determine cell fate at the single cell level. We have developed an inducible system which allows Simultaneous Imaging and Manipulation of genomic loci by Biomolecular Assemblies (SIMBA) in living cells. In SIMBA, the human heterochromatin protein 1α (HP1α) is fused to mCherry and FRB, which can be induced to form biomolecular assemblies (BAs) with FKBP-scFv, guided to specific genomic loci by a nuclease-defective Cas9 (dCas9) or a transcriptional factor (TF) carrying tandem repeats of SunTag. The induced BAs can not only enhance the imaging signals at target genomic loci using a single sgRNA, either at repetitive or non-repetitive sequences, but also recruit epigenetic modulators such as histone methyltransferase SUV39H1 to locally repress transcription. As such, SIMBA can be applied to simultaneously visualize and manipulate, in principle, any genomic locus with controllable timing in living cells.

Monocytes engineered with iSNAP inhibit human B-lymphoma progression.

Monocytes are important regulators for the maintenance of homeostasis in innate and adaptive immune system and have been reported to play important role in cancer progression. CD47-SIRPα recognition is a coinhibitory immune signal to inhibit phagocytosis in monocytes and macrophages and has been well-known as the "Don't eat me" signal. By using an approach of integrated sensing and activating proteins (iSNAPs), we have rewired the CD47-SIRPα axis to create iSNAP-M which activates pathways in engineered human monocytes (iSNAP-MC). The mRNA expression levels of the monocyte/macrophage markers CD11b, CD14, and CD31 are upregulated in iSNAP-monocytes (iSNAP-MC). With PMA induction, the iSNAP-MC-derived macrophages (iSNAP-MΦ) showed upregelation in CD86 and CD80, but not CD206. TNFα expression and secretion were also increased in iSNAP-MΦ. Furthermore, the injection of iSNAP-MC into mice bearing human B-lymphoma tumors led to the suppression of tumor progression. Therefore, the engineered monocytes, via blockage of coinhibitory immune signals by rewiring CD47-SIRPα axis, can be applied to suppress target tumors for cancer immunotherapy.

Activation of the endocannabinoid system mediates cardiac hypertrophy induced by rosiglitazone.

Rosiglitazone (RSG) is a synthetic agonist of peroxisome proliferator-activated receptor-γ (PPARγ), which plays a central role in the regulation of metabolism. Meta-analyses have suggested that RSG is associated with increased cardiovascular risk. However, the mechanisms underlying such adverse cardiac effects are still poorly understood. Here, we found that activation of PPARγ by RSG stimulated the endocannabinoid system (ECS), a membrane lipid signaling system, which induced cardiac hypertrophy. In neonatal rat cardiomyocytes, RSG increased the level of anandamide (AEA); upregulated the expression of N-acyl phosphatidylethanolamine phospholipase D (NapePLD), a key enzyme for AEA synthesis; and downregulated the expression of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of AEA. Importantly, PPARγ activation increased the expression of cannabinoid receptor type 1 (CB1) through an identified binding site for PPARγ in the CB1 promoter region. Moreover, both the in vitro and in vivo results showed that inhibition of the ECS by rimonabant, an antagonist of CB1, attenuated RSG-induced cardiac hypertrophy, as indicated by decreased expression of cardiac hypertrophy markers (ANP and BNP), deactivation of the mTOR pathway, and decreased cardiomyocyte size. Thus, these results demonstrated that the ECS functions as a novel target of PPARγ and that the AEA/CB1/mTOR axis mediates RSG-induced cardiac remodeling.

Control of the activity of CAR-T cells within tumours via focused ultrasound.

Focused ultrasound can deliver energy safely and non-invasively into tissues at depths of centimetres. Here we show that the genetics and cellular functions of chimeric antigen receptor T cells (CAR-T cells) within tumours can be reversibly controlled by the heat generated by short pulses of focused ultrasound via a CAR cassette under the control of a promoter for the heat-shock protein. In mice with subcutaneous tumours, locally injected T cells with the inducible CAR and activated via focused ultrasound guided by magnetic resonance imaging mitigated on-target off-tumour activity and enhanced the suppression of tumour growth, compared with the performance of non-inducible CAR-T cells. Acoustogenetic control of the activation of engineered T cells may facilitate the design of safer cell therapies.

An Acoustic Hotspot Tracking Algorithm for Highly Centralized Gas Temperature Distribution.

Acoustic pyrometer is expected to be a useful noninvasive method for monitoring gas temperature distribution inside a steel-making furnace. On the superficial layer above the burden of a blast furnace, most of the high-temperature gas is concentrated near the center, and tracking the position of the hotspot is critical for productivity. However, most of the existing acoustic temperature distribution reconstruction algorithms are developed with relatively uniform temperature distribution environments. Besides, their capabilities of tracking the pinnacle of temperature distribution in the region of interest (ROI) are rarely discussed. In this research, a reconstruction method of acoustic temperature tomography dedicated for highly centralized gas temperature distribution is proposed and demonstrated. The key metrics include the reproducibility of 2-D temperature distribution, the sensitivity of hotspot shift, and the accuracy of point-to-point (P2P)/peak temperature. To optimize the result of each metric, previous approaches of acoustic temperature tomography have been first evaluated. Then, the investigation of effects from the shape and size of meshes is proceeded to improve the performance. After that, a novel method to address convergence issues while using the iterative method is introduced. Consequently, the reconstruction method proposed in this article could effectively visualize the temperature map while hotspot moves to different locations. It could also sense the occurrence of a hotspot (2.56% of ROI) traveled from center to 1% of ROI's diameter. Moreover, a competitive accuracy with 5.89% and 1.46% error at P2P root-mean-square (rms) and peak temperature is achieved, respectively. Finally, a practical acoustic 2-D pyrometer consisted of 12 ultrasonic transducers arranged in a circular pattern with a 1-m width of ROI successfully detected the shift of a hotspot when the displacement of a heater reaches 5 cm.

Effect of kallikrein on microcirculation of rats with pancreatic ischemia reperfusion injury (IRI).

The common pathway for pancreatitis onset is pancreatic ischemia reperfusion injury (IRI), which plays an especially significant role in the evolution process from acute edematous pancreatitis (AP) towards severe acute pancreatitis (SAP). This study explored the effect of Kallikrein (PK) on pancreatic ischemia reperfusion injury (IRI). Male Wistar rats were taken as study objects, and a SAP -IRI combined model was established through retrograde infusion of 5% sodium taurocholate in biliopancreatic duct combining 30 min splenic artery clipping; drug intervention was carried out by pumping PK into rat caudal vein. Pancreatic microcirculation blood flow, pancreatic micro vascular permeability, hemorheological change and levels of adherence factors CD18 and CD54 were determined respectively. PK can obviously improve pancreatic microcirculation blood flow volume and velocity of IRI rats and expand arteriole; expand diameter of pancreatic blood capillary so that perfusion state tends to be stable; decrease pancreatic micro vascular permeability, reduce rat whole blood viscosity, erythrocyte deformation index and rigidity index; SAP-IRI combination reduces expression levels of white cell adhesion factor CD18 and vascular endothelial cell adhesion cell CD54 in rats. In conclusion, PK is an effective method of improving SAP pancreatic IRI microcirculation.

GHSR deficiency exacerbates cardiac fibrosis: role in macrophage inflammasome activation and myofibroblast differentiation.

AIMS: Sustained activation of ß-adrenergic signalling induces cardiac fibrosis, which marks progression to heart failure. GHSR (growth hormone secretagogue receptor) is the receptor for ghrelin, which is an orexigenic gastric hormone with newly defined cardiovascular effects. The present study determined the effects of GHSR deficiency in a mouse model of isoproterenol (ISO)-induced cardiac fibrosis and examined the underlying mechanism. METHODS AND RESULTS: Histochemical studies showed that GHSR deficiency exacerbated cardiac fibrosis. Quantitative RT-PCR, western blotting, and immunofluorescence staining demonstrated that cardiac fibroblasts isolated from GHSR-/- mice exhibited increased expression of marker genes for myofibroblast trans-differentiation (α-SMA, SM22, and calponin) upon transforming growth factor-ß treatment compared to wild-type mice. RNA-sequencing of heart transcriptomes revealed that differentially expressed genes in GHSR-/- hearts were enriched in such biological processes as extracellular matrix organization, inflammatory response, lipid metabolism, cell cycle, migration, and adhesion. Particularly, GHSR deficiency increased Wnt/ß-catenin pathway activation in ISO-induced myocardial fibrosis. In addition, loss of GHSR in macrophages instigated inflammasome activation with increased cleavage and release of interleukin-18. CONCLUSION: These results for the first time demonstrated that GHSR deficiency aggravated ISO-induced cardiac fibrosis, suggesting that GHSR was a potential target for the intervention of cardiac fibrosis.

S-nitrosation impairs KLF4 activity and instigates endothelial dysfunction in pulmonary arterial hypertension.

Krüppel-like factor 4 (KLF4) is a transcription factor with conserved zinc finger domains. As an essential regulator of vascular homeostasis, KLF4 exerts a protective effect in endothelial cells (ECs), including regulating vasodilation, inflammation, coagulation and oxidative stress. However, the underlying mechanisms modifying KLF4 activity in mediating vascular function remain poorly understood. Recently, essential roles for S-nitrosation have been implicated in many pathophysiologic processes of cardiovascular disease. Here, we demonstrated that KLF4 could undergo S-nitrosation in response to nitrosative stress in ECs, leading to the decreased nuclear localization with compromised transactivity. Mass-spectrometry and site-directed mutagenesis revealed that S-nitrosation modified KLF4 predominantly at Cys437. Functionally, KLF4 dependent vasodilatory response was impaired after S-nitrosoglutathione (GSNO) treatment. In ECs, endothelin-1 (ET-1) induced KLF4 S-nitrosation, which was inhibited by an endothelin receptor antagonist Bosentan. In hypoxia-induced rat model of pulmonary arterial hypertension (PAH), S-nitrosated KLF4 (SNO-KLF4) was significantly increased in lung tissues, along with decreased nuclear localization of KLF4. In summary, we demonstrated that S-nitrosation is a novel mechanism for the post-translational modification of KLF4 in ECs. Moreover, these findings suggested that KLF4 S-nitrosation may be implicated in the pathogenesis of vascular dysfunction and diseases such as PAH.

Inhibition of 5-Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the ß-Arrestin2-Mammalian Target of Rapamycin/p70S6K Pathway.

BACKGROUND: As a monoamine neurotransmitter, 5-hydroxytryptamine (5-HT) or serotonin modulates mood, appetite, and sleep. Besides, 5-HT also has important peripheral functions. 5-HT receptor 2B (5-HT2BR) plays a key role in cardiovascular diseases, such as pulmonary arterial hypertension and cardiac valve disease. Percutaneous intervention has been used to restore blood flow in occlusive vascular disease. However, restenosis remains a significant problem. Herein, we investigated the role of 5-HT2BR in neointimal hyperplasia, a key pathological process in restenosis. METHODS AND RESULTS: The expression of 5-HT2BR was upregulated in wire-injured mouse femoral arteries. In addition, BW723C86, a selective 5-HT2BR agonist, promoted the injury response during restenosis. 5-HT and BW723C86 stimulated migration and proliferation of rat aortic smooth muscle cells. Conversely, LY272015, a selective antagonist, attenuated the 5-HT-induced smooth muscle cell migration and proliferation. In vitro study showed that the promigratory effects of 5-HT2BR were mediated through the activation of mammalian target of rapamycin (mTOR)/p70S6K signaling in a ß-arrestin2-dependent manner. Inhibition of mammalian target of rapamycin or p70S6K mitigated 5-HT2BR-mediated smooth muscle cell migration. Mice with deficiency of 5-HT2BR showed significantly reduced neointimal formation in wire-injured arteries. CONCLUSIONS: These results demonstrated that activation of 5-HT2BR and ß-arrestin2-biased downstream signaling are key pathological processes in neointimal formation, and 5-HT2BR may be a potential target for the therapeutic intervention of vascular restenosis.

GHSR deficiency suppresses neointimal formation in injured mouse arteries.

Growth hormone secretagogue receptor (GHSR) is involved in appetite regulation and energy homeostasis. In the present study, we examined the role of GHSR in neointimal formation following vascular injury. In the mouse model of femoral artery wire injury, we found that vessel intima-to-media ratio was significantly reduced in GHSR deficiency (GHSR-/-) mice compared with that in wild-type mice. Immunohistochemical staining showed that the smooth muscle cell (SMCs) in the neointima were significantly decreased in the injured arteries of GHSR-/- mice which was associated with decreased SMC proliferation and migration. Furthermore, immunoblotting demonstrated that, in cultured rat aortic SMCs, small interfering RNA-mediated GHSR knockdown suppressed the activation of Akt and ERK1/2 signaling pathway. These findings suggested a novel role of GHSR in neointimal formation likely via promoting the proliferation and migration of SMCs involving Akt and ERK1/2 signaling. Therefore, GHSR may be a potential therapeutic target in restenosis and vascular remodeling.

Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer.

Angiogenesis, a crucial step in tumor growth and metastasis, is regulated by various pro- or anti-angiogenic factors. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, roles of tumor-derived microRNAs in regulating tumor vascularization remain to be elucidated. In this study, we found that delivery of miR-494 into human vascular endothelial cells (ECs) enhanced the EC migration and promoted angiogenesis. The angiogenic effect of miR-494 was mediated by the targeting of PTEN and the subsequent activation of Akt/eNOS pathway. Importantly, co-culture experiments demonstrated that a lung cancer cell line, A549, secreted and delivered miR-494 into ECs via a microvesicle-mediated route. In addition, we found that the expression of miR-494 was induced in the tumor cells in response to hypoxia, likely via a HIF-1α-mediated mechanism. Furthermore, a specific miR-494 antagomiR effectively inhibited angiogenesis and attenuated the growth of tumor xenografts in nude mice. Taken together, these results demonstrated that miR-494 is a novel tumor-derived paracrine signal to promote angiogenesis and tumor growth under hypoxic condition.

Peroxisome Proliferator-Activated Receptor γ Regulates the Expression of Lipid Phosphate Phosphohydrolase 1 in Human Vascular Endothelial Cells.

Lipid phosphate phosphohydrolase 1 (LPP1), a membrane ectophosphohydrolase regulating the availability of bioactive lipid phosphates, plays important roles in cellular signaling and physiological processes such as angiogenesis and endothelial migration. However, the regulated expression of LPP1 remains largely unknown. Here, we aimed to examine a role of peroxisome proliferator-activated receptor γ (PPAR γ ) in the transcriptional control of LPP1 gene expression. In human umbilical vein endothelial cells (HUVECs), quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) demonstrated that activation of PPAR γ increased the mRNA level of LPP1. Chromatin immunoprecipitation assay showed that PPAR γ binds to the putative PPAR-responsive elements (PPREs) within the 5'-flanking region of the human LPP1 gene. Genomic fragment containing 1.7-kilobase of the promoter region was cloned by using PCR. The luciferase reporter assays demonstrated that overexpression of PPAR γ and rosiglitazone, a specific ligand for PPAR γ , could significantly upregulate the reporter activity. However, site-directed mutagenesis of the PPRE motif abolished the induction. In conclusion, our results demonstrated that PPAR γ transcriptionally activated the expression of LPP1 gene in ECs, suggesting a potential role of PPAR γ in the metabolism of phospholipids.

Rosiglitazone Attenuated Endothelin-1-Induced Vasoconstriction of Pulmonary Arteries in the Rat Model of Pulmonary Arterial Hypertension via Differential Regulation of ET-1 Receptors.

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular failure and death. Activation of the endothelin (ET)-1 system has been demonstrated in plasma and lung tissue of PAH patients as well as in animal models of PAH. Recently, peroxisome proliferator-activated receptor γ (PPAR γ ) agonists have been shown to ameliorate PAH. The present study aimed to investigate the mechanism for the antivasoconstrictive effects of rosiglitazone in response to ET-1 in PAH. Sprague-Dawley rats were exposed to chronic hypoxia (10% oxygen) for 3 weeks. Pulmonary arteries from PAH rats showed an enhanced vasoconstriction in response to ET-1. Treatment with PPAR γ agonist rosiglitazone (20 mg/kg per day) with oral gavage for 3 days attenuated the vasocontractive effect of ET-1. The effect of rosiglitazone was lost in the presence of L-NAME, indicating a nitric oxide-dependent mechanism. Western blotting revealed that rosiglitazone increased ETBR but decreased ETAR level in pulmonary arteries from PAH rats. ETBR antagonist A192621 diminished the effect of rosiglitazone on ET-1-induced contraction. These results demonstrated that rosiglitazone attenuated ET-1-induced pulmonary vasoconstriction in PAH through differential regulation of the subtypes of ET-1 receptors and, thus, provided a new mechanism for the therapeutic use of PPAR γ agonists in PAH.

New paradigms in inflammatory signaling in vascular endothelial cells.

Inflammation is a basic cellular process in innate and adaptive immunity. Vascular endothelial cells play an important role in the initiation, amplification, and resolution of the inflammatory response. Deregulated inflammatory response is implicated in a variety of cardiovascular diseases such as atherosclerosis, obesity, diabetes, and hypertension. Recent studies have made significant progresses in the understanding of the complex molecular pathways that mediate the pro- and anti-inflammatory signaling in endothelial cells (ECs). Specifically, a number of macromolecular complexes termed as signalosomes have been identified to integrate the proinflammatory signaling from the membrane receptors to key transcription factors such as nuclear factor-κB (NF-κB). Inflammasomes are associated with the pattern-recognition receptors such as Toll-like receptors (TLRs), nucleotide-binding oligomerization-domain (NOD)-like receptors (NLRs) to mediate innate immunity responses. Emerging evidence has also revealed that noncoding microRNAs constitute a new class of intra- and intercellular signaling molecules to modulate inflammation in ECs. Thus this article will briefly summarize these new mechanisms with a special emphasis in the context of cardiovascular diseases.

Metabonomic profiling revealed an alteration in purine nucleotide metabolism associated with cardiac hypertrophy in rats treated with thiazolidinediones.

Thiazolidinediones (TZDs) including rosiglitazone (RSG) and pioglitazone (PIO) are synthetic agonists selective for peroxisome proliferator-activated receptor-γ (PPARγ) and have been clinically used to treat type-II diabetes as insulin sensitizers. Recent meta-analyses have shown that TZDs are associated with an increased risk for the development of heart failure. To elucidate the mechanism underlying such a cardiac adverse effect, we used a (1)H NMR-based approach to examine the metabonomic profiles in the cardiac tissues treated with RSG (15 mg/kg body weight/day) or PIO (45 mg/kg/day) for 4 weeks and found that the TZD treatments resulted in a significantly altered metabolic profile in hearts, which was associated with cardiac hypertrophy. Multivariate analysis demonstrated that TZDs led to an accumulation in adenosine monophosphate (AMP) and a depletion of inosine. Consistently, AMP kinase, a signal pathway sensitive to the change in the intracellular concentrations of AMP, was activated in the cardiac tissues from the TZDs-treated rats. Quantitative real-time reverse-transcriptase polymerase chain reaction showed a significant induction of the genes involved in the de novo synthesis of purine nucleotide but a reduction of those for the catabolism. Furthermore, the putative PPAR-responsive elements were identified in the 5'-flanking regions of the TZD-up-regulated genes such as adenylosuccinate synthase gene (Adss) and phosphoribosl pyrophosphate synthetase 1 (Prps1), and the binding of PPARγ to these motifs was confirmed by using chromatin immunoprecipitation assay. In conclusion, these results demonstrated that TZDs induced alterations in purine nucleotide metabolism in rat hearts via transcriptional regulation of the PPARγ-target genes, which may play an important role in the development of cardiac hypertrophy associated with TZDs.

Epigallocatechin-3-O-gallate, a green tea polyphenol, induces expression of pim-1 kinase via PPARγ in human vascular endothelial cells.

Pim-1 is a serine/threonine kinase and involved in cell survival and proliferation. Recently, it has been shown that pim-1 signaling pathway plays an important role in cardiovascular protection and differentiation. In this study, we sought to explore the expression of pim-1 in human vascular endothelial cells (ECs) and its regulation by epigallocatechin-3-O-gallate (EGCG), a green tea polyphenol which has anti-oxidant, anti-inflammatory and vascular protective effects. By using quantitative reverse transcriptase PCR (qRT-PCR) and Western blotting, we showed that EGCG dose-dependently increased the expression of pim-1 in cultured umbilical vein endothelial cells. Next, we showed that EGCG activated a luciferase reporter driven by peroxisome proliferators-activated receptor (PPAR)-responsive elements. The induced expression of pim-1 was inhibited in ECs pretreated with GW9662, a specific antagonist of PPARγ. In addition, pim-1 was also up-regulated in endothelial cells treated with rosiglitazone, a specific agonist for PPARγ, or those infected with the adenovirus expressing a constitutively active PPARγ. Collectively, our results provided new evidence that pim-1 can be up-regulated by EGCG via a PPARγ-mediated mechanism and may mediate its vascular protective effects.

Peroxisome proliferator-activated receptor-γ ameliorates pulmonary arterial hypertension by inhibiting 5-hydroxytryptamine 2B receptor.

An elevated plasma level of 5-hydroxytryptamine (5-HT) or upregulation of 5-HT receptor signaling or both is implicated in vascular contraction and remodeling in pulmonary arterial hypertension (PAH). Recently, peroxisome proliferator-activated receptor-γ (PPARγ) agonists have been shown to ameliorate PAH. However, their effects on the 5-HT-induced contraction of pulmonary arteries remain unknown. Here, we examined the role of PPARγ in inhibiting 5-HT2B receptor (5-HT2BR) to ameliorate PAH. Pulmonary arteries from PAH rats induced by monocrotaline or chronic hypoxia showed an enhanced vasoconstriction in response to BW723C86, a specific agonist for 5-HT2BR. Expression of 5-HT2BR was also increased in pulmonary arteries from the PAH rats, accompanied by vascular remodeling and right ventricular hypertrophy. Treatment with the PPARγ agonist rosiglitazone in vivo reversed the expression and the vasocontractive effect of 5-HT2BR as well as the thickening of pulmonary arteries. In pulmonary artery smooth muscle cells, 5-HT induced the gene expression of 5-HT2BR, which was inhibited by rosiglitazone, pioglitazone, or adenovirus-mediated overexpression of constitutively activated PPARγ. The pharmacological effect of PPARγ was through the suppression of the 5-HT-induced activator protein-1 activity. These results demonstrated the beneficial effect of PPARγ on 5-HT2BR-mediated vasocontraction, providing a new mechanism for the potential use of PPARγ agonists in PAH.