The transient receptor potential (TRP) superfamily consists of a large number of nonselective cation channels with variable degree of Ca(2+)-permeability. The 28 mammalian TRP channel proteins can be grouped into six subfamilies: canonical, vanilloid, melastatin, ankyrin, polycystic, and mucolipin TRPs. The majority of these TRP channels are expressed in different cell types including both excitable and nonexcitable cells of the cardiovascular system. Unlike voltage-gated ion channels, TRP channels do not have a typical voltage sensor, but instead can sense a variety of other stimuli including pressure, shear stress, mechanical stretch, oxidative stress, lipid environment alterations, hypertrophic signals, and inflammation products. By integrating multiple stimuli and transducing their activity to downstream cellular signal pathways via Ca(2+) entry and/or membrane depolarization, TRP channels play an essential role in regulating fundamental cell functions such as contraction, relaxation, proliferation, differentiation, and cell death. With the use of targeted deletion and transgenic mouse models, recent studies have revealed that TRP channels are involved in numerous cellular functions and play an important role in the pathophysiology of many diseases in the cardiovascular system. Moreover, several TRP channels are involved in inherited diseases of the cardiovascular system. This review presents an overview of current knowledge concerning the physiological functions of TRP channels in the cardiovascular system and their contributions to cardiovascular diseases. Ultimately, TRP channels may become potential therapeutic targets for cardiovascular diseases.
Background Supravalvular aortic stenosis (SVAS) is caused by mutations in the elastin (ELN) gene and is characterized by abnormal proliferation of vascular smooth muscle cells (SMCs) that can lead to narrowing or blockage of the ascending aorta and other arterial vessels. Availability of patient-specific SMCs may facilitate studying disease mechanisms and developing novel therapeutic interventions. Methods and Results Here, we report the development of a human induced pluripotent stem cell (iPSC) line from a patient with SVAS caused by the premature termination in exon 10 of the ELN gene due to an exon 9 4-nucleotide insertion. We showed that SVAS iPSC-derived SMCs (iPSC-SMCs) had significantly fewer organized networks of smooth muscle alpha actin (SM α-actin) filament bundles, a hallmark of mature contractile SMCs, compared to control iPSC-SMCs. Addition of elastin recombinant protein or enhancement of small GTPase RhoA signaling was able to rescue the formation of SM α-actin filament bundles in SVAS iPSC-SMCs. Cell counts and BrdU analysis revealed a significantly higher proliferation rate in SVAS iPSC-SMCs than control iPSC-SMCs. Furthermore, SVAS iPSC-SMCs migrated at a markedly higher rate to the chemotactic agent platelet-derived growth factor (PDGF) in comparison with the control iPSC-SMCs. We also provided evidence that elevated activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is required for hyper-proliferation of SVAS iPSC-SMCs. The phenotype was confirmed in iPSC-SMCs generated from a patient with deletion of elastin due to Williams-Beuren syndrome (WBS). Conclusions Thus, SVAS iPSC-SMCs recapitulate key pathological features of patients with SVAS and may provide a promising strategy to study disease mechanisms and to develop novel therapies.
BACKGROUND AND PURPOSETransient receptor potential melastatin 7 (TRPM7) is a unique channel kinase which is crucial for various physiological functions. However, the mechanism by which TRPM7 is gated and modulated is not fully understood. To better understand how modulation of TRPM7 may impact biological processes, we investigated if TRPM7 can be regulated by the phospholipids sphingosine (SPH) and sphingosine-1-phosphate (S1P), two potent bioactive sphingolipids that mediate a variety of physiological functions. Moreover, we also tested the effects of the structural analogues of SPH, N,N-dimethyl-D-erythrosphingosine (DMS), ceramides and FTY720 on TRPM7. EXPERIMENTAL APPROACHHEK293 cells stably expressing TRPM7 were used for whole-cell, single-channel and macropatch current recordings. Cardiac fibroblasts were used for native TRPM7 current recording. KEY RESULTSSPH potently inhibited TRPM7 in a concentration-dependent manner, whereas S1P and other ceramides did not produce noticeable effects. DMS also markedly inhibited TRPM7. Moreover, FTY720, an immunosuppressant and the first oral drug for treatment of multiple sclerosis, inhibited TRPM7 with a similar potency to that of SPH. In contrast, FTY720-P has no effect on TRPM7. It appears that SPH and FTY720 inhibit TRPM7 by reducing channel open probability. Furthermore, endogenous TRPM7 in cardiac fibroblasts was markedly inhibited by SPH, DMS and FTY720. CONCLUSIONS AND IMPLICATIONSThis is the first study demonstrating that SPH and FTY720 are potent inhibitors of TRPM7. Our results not only provide a new modulation mechanism of TRPM7, but also suggest that TRPM7 may serve as a direct target of SPH and FTY720, thereby mediating S1P-independent physiological/pathological functions of SPH and FTY720. LINKED ARTICLEThis article is commented on by Rohacs, pp. 1291-1293 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12070 Abbreviations FTY720, fingolimod, 2-amino-2-propane-1,3-diol hydrochloride; FTY720-P, FTY720-phosphate; S1P, sphingosine-1-phosphate; SPH, sphingosine; TRPM7, transient receptor potential melastatin 7
Cardiac fibrosis is associated with most cardiac diseases. Fibrosis is an accumulation of excessive extracellular matrix proteins (ECM) synthesized by cardiac fibroblasts and myofibroblasts. Fibroblasts are the most prevalent cell type in the heart, comprising 75% of cardiac cells. Myofibroblasts are hardly present in healthy normal heart tissue, but appear abundantly in diseased hearts. Cardiac fibroblasts are activated by a variety of pathological stimuli, such as myocardial injury, oxidative stress, mechanical stretch, and elevated autocrine-paracrine mediators, thereby undergoing proliferation, differentiation to myofibroblasts, and production of various cytokines and ECM proteins. A number of signaling pathways and bioactive molecules are involved and work in concert to activate fibroblasts and myofibroblasts in the fibrogenesis cascade. Fibroblasts and myofibroblasts are not only principal ECM producers, but also play a central role in fibrogenesis and myocardial remodeling in fibrotic heart disease. Thus, understanding the biological processes of cardiac fibroblasts will provide novel insights into the underlying mechanisms of fibrosis and provide potential targets for developing anti-fibrotic drugs. Recent studies demonstrate that Ca2+ signal is essential for fibroblast proliferation, differentiation, and ECM-protein production. This review focuses on the recent advances in understanding molecular mechanisms of Ca2+ signaling in cardiac fibrogenesis, and potential role of Ca2+-permeable channels, in particular, the transient potential (TRP) channels in fibrotic heart disease. TRP channels are highly expressed in cardiac fibroblasts. TRPM7 has been shown to be essential in TGFβ1 mediated fibrogenesis, and TRPC3 has been demonstrated to play an essential role in regulating fibroblast function. Thus, the Ca2+-permeable TRP channels may serve as potential novel targets for developing anti-fibrotic drugs.
Changes of intracellular and extracellular pH are involved in a variety of physiological and pathological processes, in which regulation of the Ca2+ release activated Ca2+ channel (ICRAC) by pH has been implicated. Ca2+ entry mediated by ICRAC has been shown to be regulated by acidic or alkaline pH. Whereas several amino acid residues have been shown to contribute to extracellular pH (pHo) sensitivity, the molecular mechanism for intracellular pH (pHi) sensitivity of Orai1/STIM1 is not fully understood. By investigating a series of mutations, we find that the previously identified residue E106 is responsible for pHo sensitivity when Ca2+ is the charge carrier. Unexpectedly, we identify that the residue E190 is responsible for pHo sensitivity when Na+ is the charge carrier. Furthermore, the intracellular mutant H155F markedly diminishes the response to acidic and alkaline pHi, suggesting that H155 is responsible for pHi sensitivity of Orai1/STIM1. Our results indicate that, whereas H155 is the intracellular pH sensor of Orai1/STIM1, the molecular mechanism of external pH sensitivity varies depending on the permeant cations. As changes of pH are involved in various physiological/pathological functions, Orai/STIM channels may be an important mediator for various physiological and pathological processes associated with acidosis and alkalinization.
Background Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. Methods Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. Results The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n = 38; PD-1 inhibitor monotherapy, n = 20; chemotherapy alone, n = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17–0.80, P = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42–0.94, P = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31–1.10, P = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45–0.83, P = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). Conclusions Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC.
Transforming growth factor (TGF)-beta1, as a candidate tumor marker, is currently of interest. In this study, serum TGF-beta1 levels in gastric cancer (GC) patients and healthy volunteers were measured using enzyme-linked immunosorbent assay (ELISA). In addition, single nucleotide polymorphisms (SNPs) of the TGF-beta1 gene at codon 10 and codon 25 were identified by means of amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and sequence analysis. Our results indicated that serum concentrations of TGF-beta1 in GC patients were significantly higher than those in the control, and positively correlated with tumor mass, invasion, metastasis, and clinical stage. The serum TGF-beta1 levels of patients recovering from radical resection were markedly lower than those before surgery. Meanwhile, no deoxyribonucleic acid (DNA) sequence variation at codon 25 of the TGF-beta1 gene was found and a TGF-beta1 gene polymorphism at codon 10 did not show obvious correlations with either TGF-beta1 expression or clinicopathological parameters of GC. Our evidence suggested that serum concentration of TGF-beta1 might be a novel tumor marker for GC and the polymorphisms of TGF-beta1 gene did not play a role as a determinant of serum TGF-beta1 concentration or as a genetic risk factor in the gastric carcinogenesis and progression.
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