The sun, cholesterol and Orai1 conspire in melanoma.

How does skin cancer become metastatic? A recent study by Gross et al (2022) reports a novel pathway by which UV radiation acts on cholesterol biosynthesis to control Ca2+ influx by Orai1, causing protein O-GlcNAcylation that promotes transformation to invasive melanoma.

PtdSer as a signaling lipid determined by privileged localization of ORP5 and ORP8 at ER/PM junctional foci to determine PM and ER PtdSer/PI(4)P ratio and cell function.

The membrane contact site ER/PM junctions are hubs for signaling pathways, including Ca2+ signaling. Phosphatidylserine (PtdSer) mediates various physiological functions; however, junctional PtdSer composition and the role of PtdSer in Ca2+ signaling and Ca2+-dependent gene regulation are not understood. Here, we show that STIM1-formed junctions are required for PI(4)P/PtdSer exchange by ORP5 and ORP8, which have reciprocal lipid exchange modes and function as a rheostat that sets the junctional PtdSer/PI(4)P ratio. Targeting the ORP5 and ORP8 and their lipid transfer ORD domains to PM subdomains revealed that ORP5 sets low and ORP8 high junctional PI(4)P/PtdSer ratio that controls STIM1-STIM1 and STIM1-Orai1 interaction and the activity of the SERCA pump to determine the pattern of receptor-evoked Ca2+ oscillations, and consequently translocation of NFAT to the nucleus. Significantly, targeting the ORP5 and ORP8 ORDs to the STIM1 ER subdomain reversed their function. Notably, changing PI(4)P/PtdSer ratio by hydrolysis of PM or ER PtdSer with targeted PtdSer-specific PLA1a1 reproduced the ORPs function. The function of the ORPs is determined both by their differential lipid exchange modes and by privileged localization at the ER/PM subdomains. These findings reveal a role of PtdSer as a signaling lipid that controls the available PM PI(4)P, the unappreciated role of ER PtdSer in cell function, and the diversity of the ER/PM junctions. The effect of PtdSer on the junctional PI(4)P level should have multiple implications in cellular signaling and functions.

Anoctamin 8 tethers endoplasmic reticulum and plasma membrane for assembly of Ca2+ signaling complexes at the ER/PM compartment.

Communication and material transfer between membranes and organelles take place at membrane contact sites (MCSs). MCSs between the ER and PM, the ER/PM junctions, are the sites where the ER Ca2+ sensor STIM1 and the PM Ca2+ influx channel Orai1 cluster. MCSs are formed by tether proteins that bridge the opposing membranes, but the identity and role of these tethers in receptor-evoked Ca2+ signaling is not well understood. Here, we identified Anoctamin 8 (ANO8) as a key tether in the formation of the ER/PM junctions that is essential for STIM1-STIM1 interaction and STIM1-Orai1 interaction and channel activation at a ER/PM PI(4,5)P2-rich compartment. Moreover, ANO8 assembles all core Ca2+ signaling proteins: Orai1, PMCA, STIM1, IP3 receptors, and SERCA2 at the ER/PM junctions to mediate a novel form of Orai1 channel inactivation by markedly facilitating SERCA2-mediated Ca2+ influx into the ER. This controls the efficiency of receptor-stimulated Ca2+ signaling, Ca2+ oscillations, and duration of Orai1 activity to prevent Ca2+ toxicity. These findings reveal the central role of MCSs in determining efficiency and fidelity of cell signaling.

The role and medical prospects of long non-coding RNAs in cardiovascular disease.

Cardiovascular disease (CVD) has reached epidemic proportions and is a leading cause of death worldwide. One of the long-standing goals of scientists is to repair heart tissue damaged by various forms of CVD such as cardiac hypertrophy, dilated cardiomyopathy, myocardial infarction, heart fibrosis, and genetic and developmental heart defects such as heart valve deformities. Damaged or defective heart tissue has limited regenerative capacity and results in a loss of functioning myocardium. Advances in transcriptomic profiling technology have revealed that long noncoding RNA (lncRNA) is transcribed from what was once considered "junk DNA." It has since been discovered that lncRNAs play a critical role in the pathogenesis of various CVDs and in myocardial regeneration. This review will explore how lncRNAs impact various forms of CVD as well as those involved in cardiomyocyte regeneration. Further, we discuss the potential of lncRNAs as a therapeutic modality for treating CVD.

Intracoronary versus intravenous glycoprotein IIb/IIIa inhibitors during primary percutaneous coronary intervention in patients with STEMI: a systematic review and meta-analysis.

BACKGROUND: Intracoronary (IC) administration of glycoprotein IIb/IIIa inhibitors (GPIs) has been studied as an adjunctive therapy to improve outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of IC administration of GPIs compared with those of intravenous (IV) administration in patients with STEMI. METHODS: We searched the MEDLINE, Embase, and Cochrane CENTRAL databases for relevant studies published before September 21, 2022. In total, 22 randomized controlled trials involving 7,699 patients were included. RESULTS: The proportions of patients achieving thrombolysis in myocardial infarction grade 3 flow, myocardial blush grade 2/3, and complete ST-segment resolution were significantly higher in the IC group than in the IV group. Major adverse cardiac events (MACE) (RR: 0.54, 95% CI: 0.37-0.80) and heart failure (RR: 0.48, 95% CI: 0.25-0.91) within 1 month were significantly lower in the IC group than in the IV group; however, after 6 months, no difference was observed in MACE risk. Additionally, the risks of death and bleeding did not differ between the two routes of administration. CONCLUSIONS: When considering adjunctive GPI administration for patients with STEMI, the IC route may offer greater benefits than the IV route in terms of myocardial reperfusion and reduced occurrence of MACE and heart failure within 1 month. Nonetheless, when making decisions for IC administration of GPIs, the absence of a benefit for bleeding risk and difficulty accessing the administration route should be considered.

Performance of a Novel CT-Derived Fractional Flow Reserve Measurement to Detect Hemodynamically Significant Coronary Stenosis.

BACKGROUND: Fractional flow reserve (FFR) based on computed tomography (CT) has been shown to better identify ischemia-causing coronary stenosis. However, this current technology requires high computational power, which inhibits its widespread implementation in clinical practice. This prospective, multicenter study aimed at validating the diagnostic performance of a novel simple CT based fractional flow reserve (CT-FFR) calculation method in patients with coronary artery disease. METHODS: Patients who underwent coronary CT angiography (CCTA) within 90 days and invasive coronary angiography (ICA) were prospectively enrolled. A hemodynamically significant lesion was defined as an FFR ≤ 0.80, and the area under the receiver operating characteristic curve (AUC) was the primary measure. After the planned analysis for the initial algorithm A, we performed another set of exploratory analyses for an improved algorithm B. RESULTS: Of 184 patients who agreed to participate in the study, 151 were finally analyzed. Hemodynamically significant lesions were observed in 79 patients (52.3%). The AUC was 0.71 (95% confidence interval [CI], 0.63-0.80) for CCTA, 0.65 (95% CI, 0.56-0.74) for CT-FFR algorithm A (P = 0.866), and 0.78 (95% CI, 0.70-0.86) for algorithm B (P = 0.112). Diagnostic accuracy was 0.63 (0.55-0.71) for CCTA alone, 0.66 (0.58-0.74) for algorithm A, and 0.76 (0.68-0.82) for algorithm B. CONCLUSION: This study suggests the feasibility of automated CT-FFR, which can be performed on-site within several hours. However, the diagnostic performance of the current algorithm does not meet the a priori criteria for superiority. Future research is required to improve the accuracy.

Efficacy and Safety of Clinically Driven Low-Dose Treatment with Direct Oral Anticoagulants in Asians with Atrial Fibrillation: a Systematic Review and Meta-analysis.

PURPOSE: Although clinically driven low-dose (CDLD) treatment with direct oral anticoagulants (DOACs) is frequently administered to Asian patients with atrial fibrillation, clinical evidence confirming its efficacy remains insufficient. We evaluated the clinical efficacy and safety of CDLD treatment with DOACs compared to on-label dose treatment in Asian patients with atrial fibrillation and assessed the differences in the baseline characteristics between patients receiving these treatments. METHODS: We searched the MEDLINE, CENTRAL, EMBASE, Web of Science, and Scopus databases for articles from inception through July 2020. RESULTS: Thirteen studies were included in this meta-analysis. The baseline characteristics of the CDLD group were significantly different from those of the standard dose (STD) and standard low-dose (SLD) groups. The incidences of thromboembolic events (risk ratio [RR] 0.46, 95% confidence interval [CI] 0.29-0.73, p < 0.001) and major bleeding (RR 0.55, 95% CI 0.35-0.87, p = 0.01) in the CDLD group were lower than those in the SLD group; however, they were comparable with those in the STD group. The incidence of a composite endpoint in the CDLD group was not significantly different from that in the STD group but was significantly lower than that in the SLD group (RR 0.50, 95% CI 0.38-0.65, p < 0.001). CONCLUSION: The clinical outcomes of CDLD treatment showed no difference compared to those of the STD treatment despite the vulnerable baseline characteristics of the CDLD group for thromboembolic and major bleeding events.

Peripheral arterial endothelial dysfunction predicts future cardiovascular events in diabetic patients with albuminuria: a prospective cohort study.

BACKGROUND: Reactive hyperemia-peripheral arterial tonometry (RH-PAT) is a noninvasive and simple test for evaluating the endothelial function. There has been sparse evidence on the usefulness of the RH-PAT index (RHI) in predicting future cardiovascular diseases among diabetic patients. METHODS: Asymptomatic diabetic patients with albuminuria were selected; their medical history and laboratory findings were evaluated every 3 to 4 months, respectively. The primary outcome was a composite of three-point major adverse cardiovascular events (3-point MACE): death from cardiovascular causes, acute coronary events, or nonfatal stroke. On the contrary, secondary outcomes included a composite of 3-point MACE, hospitalization for heart failure, or chronic kidney disease (CKD) progression. RHI was measured using the Endo-PAT2000 at the baseline. RHI < 1.67 was considered to indicate peripheral endothelial dysfunction (PED). RESULTS: In total, 149 subjects were included (mean age, 61.8 ± 9.2 years; duration of diabetes was 12 years). During the follow-up period (median, 49.7 months), of the 149 subjects, primary outcomes were detected in 12 (1 [2.3%] and 11 [10.5%] of those without and with PED, respectively). The presence of PED in baseline measurements significantly increased both primary and secondary outcomes, following adjustment for age, sex, hypertension, glycated hemoglobin, low-density lipoprotein cholesterol, triglyceride, systolic blood pressure, baseline estimated glomerular filtration rate, overt proteinuria, duration of diabetes, premedical history of ischemic events, anti-platelet agents, and smoking history (hazard ratio [HR]: 10.95; 95% confidence interval CI 1.00-119.91 for the primary outcome; HR, 4.12; 95% CI 1.37-12.41 for secondary outcome). In addition, PED could predict secondary outcomes independent of the risk score according to the American College of Cardiology/American Heart Association (HR: 3.24; 95% CI 1.14-9.17). CONCLUSIONS: PED can independently predict future cardiovascular events among diabetic patients with albuminuria.

Three-year clinical outcome of biodegradable hybrid polymer Orsiro sirolimus-eluting stent and the durable biocompatible polymer Resolute Integrity zotarolimus-eluting stent: A randomized controlled trial.

AIMS: We compared long-term clinical outcomes between patients treated with Orsiro sirolimus-eluting stent (O-SES) and those treated with durable biocompatible polymer Resolute Integrity zotarolimus-eluting stent (R-ZES). METHODS AND RESULTS: The ORIENT trial was a randomized controlled noninferiority trial to compare angiographic outcomes between O-SES and R-ZES. We performed a post hoc analysis of 3-year clinical outcomes and included 372 patients who were prospectively enrolled and randomly assigned to O-SES (n = 250) and R-ZES (n = 122) groups in a 2:1 ratio. The primary endpoint was target lesion failure defined as a composite of cardiac death, nonfatal myocardial infarction, and target lesion revascularization. At 3 years, target lesion failure occurred in 4.7% and 7.8% of O-SES and R-ZES groups, respectively (hazard ratio, 0.58; 95% confidence intervals, 0.24-1.41; p = .232 by log-rank test). Secondary endpoints including cardiac death, myocardial infarction, and target lesion revascularization showed no significant differences between the groups. Stent thrombosis occurred in two patients in R-ZES group (0.0% vs. 1.6%, p = .040). CONCLUSION: This study confirms long-term safety and efficacy of the two stents. We found a trend for lower target lesion failure with O-SES compared to R-ZES, although statistically insignificant.

Association of Plasma Marker of Oxidized Lipid with Histologic Plaque Instability in Patients with Peripheral Artery Disease.

BACKGROUND: The association between oxidized low-density lipoprotein (OxLDL) and plaque instability in coronary and carotid artery disease is well established. However, the association between OxLDL and the histologic changes of plaque in peripheral artery disease has not been clearly elucidated. This study aims to investigate the association between plasma OxLDL and histologic plaque instability in patients with peripheral artery disease. METHODS: Prospectively obtained plaques from 48 patients who underwent endovascular atherectomy (n = 20), surgical endarterectomy (n = 9), or bypass surgery (n = 19) for treatment of atherosclerotic femoropopliteal artery disease were evaluated for histologic fibrosis, sclerosis, calcification, necrosis, cholesterol cleft, and foamy macrophages using hematoxylin and eosin, oil red O, and immunohistochemical staining. Unstable plaques were defined as plaques that were positive for foamy macrophages and with lipid content of more than 10% of the total plaque area. Plasma OxLDL levels were measured using an enzyme-linked immunosorbent assay (Mercodia AB, Uppsala, Sweden). RESULTS: Of the 48 patients, 26 (54%) had unstable plaques. The unstable plaque group was younger, had fewer angiographic total occlusions, less calcification, and more CD68-positive and LOX-1-positive cells than the stable plaque group. Plasma OxLDL levels were significantly higher in the unstable plaque group than in the stable plaque group (57.4 ± 13.9 vs. 47.2 ± 13.6 U/L, P = 0.014). Multivariate analysis revealed that plasma OxLDL level, smoking, angiographic nontotal occlusion, and statin nonuse were independent predictors of unstable plaque. CONCLUSIONS: Among patients with peripheral artery disease, the histologic instability of femoropopliteal plaque was independently associated with high plasma OxLDL, smoking, nontotal occlusion, and statin nonuse. Further large-scale studies are necessary to evaluate the role of noninvasive OxLDL measurement for predicting plaque instability and future adverse vascular event.

Lipids at membrane contact sites: cell signaling and ion transport.

Communication between organelles is essential to coordinate cellular functions and the cell's response to physiological and pathological stimuli. Organellar communication occurs at membrane contact sites (MCSs), where the endoplasmic reticulum (ER) membrane is tethered to cellular organelle membranes by specific tether proteins and where lipid transfer proteins and cell signaling proteins are located. MCSs have many cellular functions and are the sites of lipid and ion transfer between organelles and generation of second messengers. This review discusses several aspects of MCSs in the context of lipid transfer, formation of lipid domains, generation of Ca2+ and cAMP second messengers, and regulation of ion transporters by lipids.

The clinical impact of sex differences on ischemic postconditioning during primary percutaneous coronary intervention: a POST (the effects of postconditioning on myocardial reperfusion in patients with ST-segment elevation myocardial infarction) substudy.

The POST (the effects of postconditioning on myocardial reperfusion in patients with ST-Segment elevation myocardial infarction) study showed that ischemic postconditioning did not improve myocardial reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). However, it has not been determined whether postconditioning is effective in women. This study sought to evaluate the impact of sex differences on ischemic postconditioning during the primary PCI. We analyzed clinical outcomes at 1 year in the 537 men and 163 women with STEMI, who were randomized to the postconditioning or to the conventional PCI group. Women were older, had higher rates of hypertension, were less likely to be current smokers, and had longer symptom-to-reperfusion time. The rate of major adverse cardiac events (MACE: a composite of death, myocardial infarction, severe heart failure, stent thrombosis, or target vessel revascularization) at 1 year was higher in women compared to men (9.8% vs. 5.4%, p = 0.044). MACE was significantly higher in women compared to men in the postconditioning group (12.2% vs. 5.4%, p = 0.042), but not in the conventional PCI group (7.9% vs. 5.4%, p = 0.391). However, women was not an independent predictor after adjusting baseline risk factors, angiographic and procedural parameters (HR 2.67, 95% CI 0.68-10.5, p = 0.158). Despite women having more adverse clinical characteristics, their prognosis was similar to men in the conventional group. Although women showed a higher rate of the MACE compared to men, women were not an independent predictor in the postconditioning group.

The Prevention of Contrast Induced Nephropathy by Sarpogrelate: a Prospective Randomized Controlled Clinical Trial.

BACKGROUND: Although some strategies are used for prophylaxis of contrast induced nephropathy, their efficacy is not fully established. Sarpogrelate can relieve vasospasm and have anti-inflammatory action. This study examined whether sarpogrelate reduces the incidence of contrast induced nephropathy (CIN) or subsequent renal impairment during four weeks after coronary angiography compared with a control group. METHODS: Seventy-four participants with chronic renal failure were randomly assigned to the sarpogrelate or control group. Patients assigned to the sarpogrelate group received oral saporogelate from 24 hours before contrast exposure up to one month after contrast exposure. The primary outcome of this study was the incidence of CIN within 48 hours after exposure to the contrast agent. RESULTS: Thirty-one subjects in the control group and 35 subjects in the sarpogrelate group were used for the analysis. Cumulative CIN occurred numerically more at 48 hours in the sarpogrelate group and less at one month without statistical significance (11.4% vs. 6.5% at 48 hours and 11.4% vs. 16.1% at one month, respectively). Baseline renal function was similar in both groups, but the estimated glomerular filtration rate (eGFR) was lower in the sarpogrelate group at 12 and 48 hours compared with the control group (45.6 vs. 54.7 mL/min/1.73m²; P = 0.023 and 39.9 vs. 50.6 mL/min/1.73m²; P = 0.020, respectively). At one month, the eGFR became comparable between the two groups because the eGFR was aggravated in the control group and maintained in the sarpogrelate group. CONCLUSION: This study failed to demonstrate that sarpogrelate has a renoprotective effect against contrast induced acute kidney injury. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01165567.

Monomerization and ER Relocalization of GRASP Is a Requisite for Unconventional Secretion of CFTR.

Induction of endoplasmic reticulum (ER)-to-Golgi blockade or ER stress induces Golgi reassembly stacking protein (GRASP)-mediated, Golgi-independent unconventional cell-surface trafficking of the folding-deficient ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR). However, molecular mechanisms underlying this process remain elusive. Here, we show that phosphorylation-dependent dissociation of GRASP homotypic complexes and subsequent relocalization of GRASP to the ER play a critical role in the unconventional secretion of CFTR. Immunolocalization analyses of mammalian cells revealed that the Golgi protein GRASP55 was redistributed to the ER by stimuli that induce unconventional secretion of ΔF508-CFTR, such as induction of ER-to-Golgi blockade by the Arf1 mutant. Notably, the same stimuli also induced phosphorylation of regions near the C-terminus of GRASP55 and dissociation of GRASP homomultimer complexes. Furthermore, phosphorylation-mimicking mutations of GRASP55 induced the monomerization and ER relocalization of GRASP55, and these changes were nullified by phosphorylation-inhibiting mutations. These results provide mechanistic insights into how GRASP accesses the ER-retained ΔF508-CFTR and mediates the ER stress-induced unconventional secretion pathway.

Fractional Flow Reserve and Cardiac Events in Coronary Artery Disease: Data From a Prospective IRIS-FFR Registry (Interventional Cardiology Research Incooperation Society Fractional Flow Reserve).

BACKGROUND: We evaluated the prognosis of deferred and revascularized coronary stenoses after fractional flow reserve (FFR) measurement to assess its revascularization threshold in clinical practice. METHODS: The IRIS-FFR registry (Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve) prospectively enrolled 5846 patients with ≥1coronary lesion with FFR measurement. Revascularization was deferred in 6468 lesions and performed in 2165 lesions after FFR assessment. The primary end point was major adverse cardiac events (cardiac death, myocardial infarction, and repeat revascularization) at a median follow-up of 1.9 years and analyzed on a per-lesion basis. A marginal Cox model accounted for correlated data in patients with multiple lesions, and a model to predict per-lesion outcomes was adjusted for confounding factors. RESULTS: For deferred lesions, the risk of major adverse cardiac events demonstrated a significant, inverse relationship with FFR (adjusted hazard ratio, 1.06; 95% confidence interval, 1.05-1.08; P<0.001). However, this relationship was not observed in revascularized lesions (adjusted hazard ratio, 1.00; 95% confidence interval, 0.98-1.02; P=0.70). For lesions with FFR ≥0.76, the risk of major adverse cardiac events was not significantly different between deferred and revascularized lesions. Conversely, in lesions with FFR ≤0.75, the risk of major adverse cardiac events was significantly lower in revascularized lesions than in deferred lesions (for FFR 0.71-0.75, adjusted hazard ratio, 0.47; 95% confidence interval, 0.24-0.89; P=0.021; for FFR ≤0.70, adjusted hazard ratio 0.47; 95% confidence interval, 0.26-0.84; P=0.012). CONCLUSIONS: This large, prospective registry showed that the FFR value was linearly associated with the risk of cardiac events in deferred lesions. In addition, revascularization for coronary artery stenosis with a low FFR (≤0.75) was associated with better outcomes than the deferral, whereas for a stenosis with a high FFR (≥0.76), medical treatment would be a reasonable and safe treatment strategy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01366404.

Comparison of drug-eluting stents and drug-coated balloon for the treatment of drug-eluting coronary stent restenosis: A randomized RESTORE trial.

BACKGROUND: This study sought to evaluate the optimal treatment for in-stent restenosis (ISR) of drug-eluting stents (DESs). METHODS: This is a prospective, multicenter, open-label, randomized study comparing the use of drug-eluting balloon (DEB) versus second-generation everolimus-eluting stent for the treatment of DES ISR. The primary end point was in-segment late loss at 9-month routine angiographic follow-up. RESULTS: A total of 172 patients were enrolled, and 74 (43.0%) patients underwent the angiographic follow-up. The primary end point was not different between the 2 treatment groups (DEB group 0.15±0.49 mm vs DES group 0.19±0.41 mm, P=.54). The secondary end points of in-segment minimal luminal diameter (MLD) (1.80±0.69 mm vs 2.09±0.46 mm, P=.03), in-stent MLD (1.90±0.71 mm vs 2.29±0.48 mm, P=.005), in-segment percent diameter stenosis (34%±21% vs 26%±15%, P=.05), and in-stent percent diameter stenosis (33%±21% vs 21%±15%, P=.002) were more favorable in the DES group. The composite of death, myocardial infarction, or target lesion revascularization at 1 year was comparable between the 2 groups (DEB group 7.0% vs DES group 4.7%, P=.51). CONCLUSIONS: Treatment of DES ISR using DEB or second-generation DES did not differ in terms of late loss at 9-month angiographic follow-up, whereas DES showed better angiographic results regarding minimal MLD and percent diameter stenosis. Both treatment strategies were safe and effective up to 1year after the procedure.

Overexpression of WNK1 in POMC-expressing neurons reduces weigh gain via WNK4-mediated degradation of Kir6.2.

"With no lysine" (WNK) kinases have been shown to regulate various ion transporters in various tissues, but studies on the function of WNK kinases in the brain have been limited. In this study, we discovered that WNK1 and WNK4 in POMC-expressing neuronal cells in WNK1 overexpressed transgenic mice (WNK1 TG) decrease appetite via degradation of Kir6.2. Weight gain after 20 weeks of age was delayed in WNK1 TG mice as a result of reduced food intake. Expression of WNK1 and proopiomelanocortin (POMC) was higher in POMC-expressing neurons in the hypothalamus of WNK1 TG mice than in WT mice. Immunostaining of serial sections of the hypothalamus revealed that POMC-expressing neurons were smaller in WNK1 TG mice than in WT mice. In addition, expression of Kir6.2 was significantly reduced in WNK1 TG mice. Overexpression and knockdown of WNK4 demonstrated that WNK4 regulates protein expression of Kir6.2 via protein-protein interaction. Accordingly, reduced age-dependent weight gain of WNK1 TG mice seems to be related with the decreased Kir6.2 expression via WNK1- and WNK4-regulated protein stability of Kir6.2.

Endothelial function estimated by digital reactive hyperemia in patients with atherosclerotic risk factors or coronary artery disease.

Due to the complex profile of atherosclerotic risk factors, an integrated analysis of a specific individual is difficult. Endothelial function reflects a composite of various risk factors, and may be used as an optimal tool to estimate the overall atherosclerotic risk. In this study, we investigated the value of digital Reactive Hyperemia Index (RHI) in an actual population with multiple atherosclerotic risk factors or coronary artery disease (CAD). A total of 417 patients from the Seoul National University Boramae Medical Center RHI registry were enrolled in this study. Patients were enrolled from January, 2013 to July, 2016. RHI was measured using the EndoPAT2000 system (Itamiar Medical Inc. Israel). The mean value of RHI was 1.67 ± 0.48 in total study population. Among various atherosclerotic risk factors, RHI was significantly lower in older (> 60 years) patients, diabetics, smokers' patients on statin therapy, and those with coronary or cerebrovascular disease. Most of these findings were consistent after adjustment with multiple regression analysis. RHI was significantly associated with CAD, with a hazard ratio of 1.80 (95% confidence interval 1.15-2.80, p = 0.010). In the subgroup with CAD, current smoking was the only finding showing a lower RHI. Brachial-ankle pulse wave velocity, which is a surrogate marker of arterial atherosclerotic change, was not correlated with RHI in patients with clinically significant atherosclerotic disease. RHI was significantly reduced by major atherosclerotic risk factors and in clinical atherosclerotic disease. RHI may reflect a composite effect of risk factors pertaining to the endothelial function.

Gender Difference in the Association between Aortic Pulse Pressure and Left Ventricular Filling Pressure in the Elderly: An Invasive Hemodynamic Study.

BACKGROUND: This study was conducted to determine the association between aortic pulse pressure (APP) and left ventricular (LV) filling pressure in the elderly of both genders. METHODS: A total of 211 stable elderly subjects (age ≥65 years, mean age 72.1 ± 5.2 years, 53.6% women) who underwent invasive coronary angiography (ICA) for the evaluation of coronary artery disease (CAD) were prospectively investigated. APP was measured in the ascending aorta using a pigtail catheter immediately before ICA. E/e', reflecting LV filling pressure, was assessed by transthoracic echocardiography. RESULTS: There were positive linear correlations between APP and E/e' in both genders, but the correlation power was stronger in women than in men (r = 0.402, P <.001 vs r = 0.208, P = .040). The significance of this association between APP and E/e' remained after controlling for potential confounders in multiple linear regression analysis in women (ß = 0.359, P <.001), but not in men (r = 0.139, P = .108). CONCLUSIONS: Invasively measured APP is independently associated with E/e' in elderly women, but not in elderly men undergoing ICA. Aortic stiffness may be a potential mechanism for more prevalent LV diastolic dysfunction and heart failure with preserved ejection fraction in elderly women.

STIM-TRP Pathways and Microdomain Organization: Ca2+ Influx Channels: The Orai-STIM1-TRPC Complexes.

Ca2+ influx by plasma membrane Ca2+ channels is the crucial component of the receptor-evoked Ca2+ signal. The two main Ca2+ influx channels of non-excitable cells are the Orai and TRPC families of Ca2+ channels. These channels are activated in response to cell stimulation and Ca2+ release from the endoplasmic reticulum (ER). The protein that conveys the Ca2+ content of the ER to the plasma membrane is the ER Ca2+ sensor STIM1. STIM1 activates the Orai channels and is obligatory for channel opening. TRPC channels can function in two modes, as STIM1-dependent and STIM1-independent. When activated by STIM1, both channel types function at the ER/PM (plasma membrane) junctions. This chapter describes the properties and regulation of the channels by STIM1, with emphasis how and when TRPC channels function as STIM1-dependent and STIM1-independent modes and their unique Ca2+-dependent physiological functions that are not shared with the Orai channels.