Association Between Vascular Adhesion Protein-1 (VAP-1) and MACE in Patients with Coronary Heart Disease: A Cohort Study.

Background: Vascular adhesion protein-1 (VAP-1), an inflammation-inducible endothelial cell molecule, was reported to be implicated in a variety of cardiovascular diseases. However, the clinical significance of circulating VAP-1 levels in patients with coronary heart disease (CHD) remains less studied. Patients and Methods: We retrospectively analyzed clinical data of 336 hospitalized patients in the Second Affiliated Hospital of Soochow University from May 2020 to September 2022, 174 of which were diagnosed with CHD. Serum VAP-1 was measured by enzyme-linked immunosorbent assay at enrollment. The primary end point of this study was the occurrence of major adverse cardiovascular events (MACE). The coronary stenosis and clinical manifestations of CHD were assessed and recorded from medical records or follow-up calls. The relevant results were obtained, and the reliability of the conclusions was verified through regression analysis, curve fitting, and survival curve. Results: After adjusting for potential confounders, higher serum VAP-1 level was associated with increased risk of MACE in patients with CHD [(HR = 5.11, 95% CI = 1.02-25.59), (HR = 5.81, 95% CI = 1.16-29.11)]. The results of curve fitting and survival analysis were consistent with those of regression analysis. However, no significant association was observed between VAP-1 and MACE in the entire study population [(HR = 5.11, 95% CI = 0.41-1.93), (HR = 1.17, 95% CI = 0.52-2.62)]. Furthermore, the level of VAP-1 did not show a significant correlation with coronary stenosis and the clinical manifestations of CHD. Conclusion: These findings suggested that CHD patients with higher serum levels of VAP-1 are at a higher risk of adverse cardiovascular outcomes.

Principal neurons in the olfactory cortex mediate bidirectional modulation of seizures.

Although the piriform cortex (PC) has been previously implicated as a critical node for seizure generation and propagation, the underlying neural mechanism has remained unclear. Here, we found increased excitability in PC neurons during amygdala kindling acquisition. Optogenetic or chemogenetic activation of PC pyramidal neurons promoted kindling progression, whereas inhibition of these neurons retarded seizure activities induced by electrical kindling in the amygdala. Furthermore, chemogenetic inhibition of PC pyramidal neurons alleviated the severity of kainic acid-induced acute seizures. These results demonstrate that PC pyramidal neurons bidirectionally modulate seizures in temporal lobe epilepsy, providing evidence for the efficacy of PC pyramidal neurons as a potential therapeutic target for epileptogenesis. KEY POINTS: While the piriform cortex (PC) is an important olfactory centre critically involved in olfactory processing and plays a crucial role in epilepsy due to its close connection with the limbic system, how the PC regulates epileptogenesis is largely unknown. In this study, we evaluated the neuronal activity and the role of pyramidal neurons in the PC in the mouse amygdala kindling model of epilepsy. PC pyramidal neurons are hyperexcited during epileptogenesis. Optogenetic and chemogenetic activation of PC pyramidal neurons significantly promoted seizures in the amygdala kindling model, whereas selective inhibition of these neurons produced an anti-epileptic effect for both electrical kindling and kainic acid-induced acute seizures. The results of the present study indicate that PC pyramidal neurons bidirectionally modulate seizure activity.

Amyloid ß oligomers disrupt piriform cortical output via a serotonergic pathway.

Although olfactory deficits have been found in patients with early-stage Alzheimer's disease (AD), the underlying mechanisms remain unclear. Here we investigated whether and how human amyloid ß (Aß) oligomers affect neural activity in the piriform cortex (PC) slices of adult mice. We found that oligomeric Aß1-42 decreased the excitability of pyramidal neurons in the anterior PC. The effect was not blocked by glutamate or GABAA receptor antagonists, suggesting that Aß1-42-induced hypoactivity is independent of glutamatergic and GABAergic transmission. Interestingly, the hypoexcitability was occluded by serotonin (5-HT) and blocked by antagonists of 5-HT2C receptors, phospholipase C (PLC), and calcium-activated potassium (BK) channels. Furthermore, Aß1-42 oligomers failed to increase K+-channel currents in the presence of a BK channel blocker. Finally, 5-HT2C receptor antagonist improved olfactory memory and odor discrimination in APP/PS1 mice. The above data indicate that Aß disrupts olfactory information output from the PC via the 5-HT-5-HT2C receptor-PLC-BK channel pathway. This study reveals that serotonergic modulation is a potential novel therapeutic target for olfactory damage in AD.

YB1 dephosphorylation attenuates atherosclerosis by promoting CCL2 mRNA decay.

Chronic inflammation is a key pathological process in atherosclerosis. RNA binding proteins (RBPs) have been reported to play an important role in atherosclerotic plaque formation, and they could regulate the expression of inflammatory factors by phosphorylation modification. Y-box binding protein 1 (YB1) is an RBP that has participated in many inflammatory diseases. Here, we found an increased expression of phosphorylated YB1 (pYB1) in atherosclerotic plaques and demonstrated that YB1 dephosphorylation reduced lipid accumulation and lesion area in the aorta in vivo. Additionally, we found that inflammatory cytokines were downregulated in the presence of YB1 dephosphorylation, particularly CCL2, which participates in the pathogenesis of atherosclerosis. Furthermore, we demonstrated that CCL2 mRNA rapid degradation was mediated by the glucocorticoid receptor-mediated mRNA decay (GMD) process during YB1 dephosphorylation, which resulted in the downregulation of CCL2 expression. In conclusion, YB1 phosphorylation affects the development of atherosclerosis through modulating inflammation, and targeting YB1 phosphorylation could be a potential strategy for the treatment of atherosclerosis by anti-inflammation.

Performance analysis of optical spatial modulation over a correlated gamma-gamma turbulence channel.

In this paper, theoretical closed expressions for the symbol error rate (SER) of two optical spatial modulation (OSM) schemes in a free-space optical (FSO) communication system-optical spatial pulse amplitude modulation (OSPAM) and optical spatial pulse position modulation (OSPPM)-over correlated gamma-gamma fading channels are derived. To study practical optical channels affected by atmospheric eddies, the effect of arbitrary atmospheric channel correlation is considered particularly, and it is shown that the correlation can degrade system performance. The parameters of atmospheric turbulence and the number of optical antennas are also under consideration in performance analysis of the FSO multiple input, multiple output system. All analytical results are validated with Monte Carlo simulations, which clearly illustrate the effect of spatial constellation and signal constellation on the average SER. In addition, it is shown by comparison that turbulence fluctuation and channel correlation have less influence on the OSPPM system than the OSPAM system. Overall, the framework proposed in this paper is proven to be effective and conducive to algorithm research on reducing the effect of correlated channels on OSM FSO systems.

Allergic asthma aggravates angiotensin â ¡-induced cardiac remodeling in mice.

Cardiovascular disease remains the leading cause of death globally, and heart failure (HF) represents its terminal stage. Asthma, one of the most common chronic diseases, has been reported to be associated with an increased risk of cardiovascular disease. However, the link between asthma and HF has rarely been studied, and the possible mechanisms by which asthma affects HF are unclear. This study aimed to explore the influence of asthma on HF and the possible mechanisms. We analyzed data from the National Health and Nutrition Examination Survey and found a higher prevalence of HF among asthmatic individuals, and identified an independent association between HF and asthma. Subsequently, we produced mice with concurrent ovalbumin (OVA) sensitization-induced allergic asthma and angiotensin Ⅱ infusion-induced cardiac remodeling to explore the effect of asthma on cardiac remodeling in vivo. The results showed that OVA-induced asthma impaired heart function and aggravated cardiac remodeling in mice. We also found that OVA sensitization increased the expression levels of immunoglobulin E (IgE) in serum and IgE receptor (FcεR1) in the heart, and enhanced the activation of downstream signaling molecules of IgE-FcεR1 in the heart. Importantly, blockage of IgE-FcεR1 using FcεR1-deficient mice or an anti-IgE antibody prevented asthma-induced decline of cardiac function, and alleviated cardiac remodeling. These findings demonstrate the adverse effects of allergic asthma on the heart, and suggest the potential application of anti-IgE therapy in the treatment of asthma complicated with heart conditions.

MK2206 attenuates atherosclerosis by inhibiting lipid accumulation, cell migration, proliferation, and inflammation.

Cardiovascular disease is a common comorbidity in patients with cancer, and the main leading cause of noncancer-related deaths in cancer survivors. Considering that current antitumor drugs usually induce cardiovascular injury, the quest for developing new antitumor drugs, especially those with cardiovascular protection, is crucial for improving cancer prognosis. MK2206 is a phase II clinical anticancer drug and the role of this drug in cardiovascular disease is still unclear. Here, we revealed that MK2206 significantly reduced vascular inflammation, atherosclerotic lesions, and inhibited proliferation of vascular smooth muscle cell in ApoE-/- mice in vivo. We demonstrated that MK2206 reduced lipid accumulation by promoting cholesterol efflux but did not affect lipid uptake and decreased inflammatory response by modulating inflammation-related mRNA stability in macrophages. In addition, we revealed that MK2206 suppressed migration, proliferation, and inflammation in vascular smooth muscle cells. Moreover, MK2206 inhibited proliferation and inflammation of endothelial cells. The present results suggest that MK2206, as a promising drug in clinical antitumor therapy, exhibits anti-inflammatory and antiatherosclerotic potential. This report provides a novel strategy for the prevention of cardiovascular comorbidities in cancer survivors.

ErbB4 in parvalbumin-positive interneurons mediates proactive interference in olfactory associative reversal learning.

Consolidated memories influence later learning and cognitive processes when new information is overlapped with previous events. To reveal which cellular and molecular factors are associated with this proactive interference, we challenged mice with odor-reward associative learning followed by a reversal-learning task. The results showed that genetical ablation of ErbB4 in parvalbumin (PV)-positive interneurons improved performance in reversal-learning phase, with no alteration in learning phase, supporting that PV interneuron ErbB4 is required for proactive interference. Mechanistically, olfactory learning promoted PV interneuron excitatory synaptic plasticity and direct binding of ErbB4 with presynaptic Neurexin1ß (NRXN1ß) and postsynaptic scaffold PSD-95 in the prefrontal cortex. Interrupting ErbB4-NRXN1ß interaction impaired network activity-driven excitatory inputs and excitatory synaptic transmission onto PV interneurons. Neuronal activity-induced ErbB4-PSD-95 association facilitated transsynaptic binding of ErbB4-NRXN1ß and excitatory synapse formation in ErbB4-positive interneurons. Furthermore, ErbB4-NRXN1ß binding was responsible for the activity-regulated activation of ErbB4 and extracellular signal-regulated kinase (ERK) 1/2 in PV interneurons, as well as synaptic plasticity-related expression of brain-derived neurotrophic factor (BDNF). Correlatedly, blocking ErbB4-NRXN1ß coupling in the medial prefrontal cortex of adult mice facilitated reversal learning of an olfactory associative task. These findings provide novel insight into the physiological role of PV interneuron ErbB4 signaling in cognitive processes and reveal an associative learning-related transsynaptic NRXN1ß-ErbB4-PSD-95 complex that affects the ERK1/2-BDNF pathway and underlies local inhibitory circuit plasticity and proactive interference.

GABAA receptor agonist muscimol rescues inhibitory microcircuit defects in the olfactory bulb and improves olfactory function in APP/PS1 transgenic mice.

Olfactory damage develops at the early stages of Alzheimer's disease (AD). While amyloid-ß (Aß) oligomers are shown to impair inhibitory circuits in the olfactory bulb (OB), its underlying mechanisms remain unclear. Here, we investigated the olfactory dysfunction due to impaired inhibitory transmission to mitral cells (MCs) of the OB in APP/PS1 mice. Using electrophysiological studies, we found that MCs exhibited increased spontaneous firing rates as early as 3 months, much before development of Aß deposits in the brain. Furthermore, the frequencies but not amplitudes of MC inhibitory postsynaptic currents decreased markedly, suggesting that presynaptic GABA release is impaired while postsynaptic GABAA receptor responses remain intact. Notably, muscimol, a GABAA receptor agonist, improved odor identification and discrimination behaviors in APP/PS1 mice, reduced MC basal firing activity, and rescued inhibitory circuits along with reducing the Aß burden in the OB. Our study links the presynaptic deficits of GABAergic transmission to olfactory dysfunction and subsequent AD development and implicates the therapeutic potential of maintaining local inhibitory microcircuits against early AD progression.

Elevated IgE promotes cardiac fibrosis by suppressing miR-486a-5p.

Rationale: Cardiac fibrosis is an important feature of cardiac remodeling and is a hallmark of heart failure. Recent studies indicate that elevated IgE plays a causal role in pathological cardiac remodeling. However, the underlying mechanism of how IgE promotes cardiac fibrosis has not been fully elucidated. Methods and Results: To explore the function of IgE in cardiac fibrosis, we stimulated mouse primary cardiac fibroblasts (CFs) with IgE and found that both IgE receptor (FcεR1) and fibrosis related proteins were increased after IgE stimulation. Specific deletion of FcεR1 in CFs alleviated angiotensin II (Ang II)-induced cardiac fibrosis in mice. To investigate the mechanisms underlying the IgE-mediated cardiac fibrosis, deep miRNA-seq was performed. Bioinformatics and signaling pathway analysis revealed that IgE upregulated Col1a1 and Col3a1 expression in CFs by repressing miR-486a-5p, with Smad1 participating downstream of miR-486a-5p in this process. Lentivirus-mediated overexpression of miR-486a-5p was found to alleviate Ang II-induced myocardial interstitial fibrosis in mice. Moreover, miR-486-5p serum levels were lower in patients with heart failure than in healthy controls, and were negatively correlated with NT-proBNP levels. Conclusions: Our study demonstrates that elevated IgE promotes pathological cardiac fibrosis by modulating miR-486a-5p and downstream factors, such as Smad1. These findings suggest new targets for pathological cardiac fibrosis intervention.

Distinct Characteristics of Odor-evoked Calcium and Electrophysiological Signals in Mitral/Tufted Cells in the Mouse Olfactory Bulb.

Fiber photometry is a recently-developed method that indirectly measures neural activity by monitoring Ca2+ signals in genetically-identified neuronal populations. Although fiber photometry is widely used in neuroscience research, the relationship between the recorded Ca2+ signals and direct electrophysiological measurements of neural activity remains elusive. Here, we simultaneously recorded odor-evoked Ca2+ and electrophysiological signals [single-unit spikes and local field potentials (LFPs)] from mitral/tufted cells in the olfactory bulb of awake, head-fixed mice. Odors evoked responses in all types of signal but the response characteristics (e.g., type of response and time course) differed. The Ca2+ signal was correlated most closely with power in the ß-band of the LFP. The Ca2+ signal performed slightly better at odor classification than high-γ oscillations, worse than single-unit spikes, and similarly to ß oscillations. These results provide new information to help researchers select an appropriate method for monitoring neural activity under specific conditions.

Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction.

BACKGROUND: Immunoglobulin E (IgE) belongs to a class of immunoglobulins involved in immune response to specific allergens. However, the roles of IgE and IgE receptor (FcεR1) in pathological cardiac remodeling and heart failure are unknown. METHODS: Serum IgE levels and cardiac FcεR1 expression were assessed in diseased hearts from human and mouse. The role of FcεR1 signaling in pathological cardiac remodeling was explored in vivo by FcεR1 genetic depletion, anti-IgE antibodies, and bone marrow transplantation. The roles of the IgE-FcεR1 pathway were further evaluated in vitro in primary cultured rat cardiomyocytes and cardiac fibroblasts (CFs). RNA sequencing and bioinformatic analyses were used to identify biochemical changes and signaling pathways that are regulated by IgE/FcεR1. RESULTS: Serum IgE levels were significantly elevated in patients with heart failure as well as in 2 mouse cardiac disease models induced by chronic pressure overload via transverse aortic constriction and chronic angiotensin II infusion. Interestingly, FcεR1 expression levels were also significantly upregulated in failing hearts from human and mouse. Blockade of the IgE-FcεR1 pathway by FcεR1 knockout alleviated transverse aortic constriction- or angiotensin II-induced pathological cardiac remodeling or dysfunction. Anti-IgE antibodies (including the clinical drug omalizumab) also significantly alleviated angiotensin II-induced cardiac remodeling. Bone marrow transplantation experiments indicated that IgE-induced cardiac remodeling was mediated through non-bone marrow-derived cells. FcεR1 was found to be expressed in both cardiomyocytes and CFs. In cultured rat cardiomyocytes, IgE-induced cardiomyocyte hypertrophy and hypertrophic marker expression were abolished by depleting FcεR1. In cultured rat CFs, IgE-induced CF activation and matrix protein production were also blocked by FcεR1 deficiency. RNA sequencing and signaling pathway analyses revealed that transforming growth factor-ß may be a critical mediator, and blocking transforming growth factor-ß indeed alleviated IgE-induced cardiomyocyte hypertrophy and cardiac fibroblast activation in vitro. CONCLUSIONS: Our findings suggest that IgE induction plays a causative role in pathological cardiac remodeling, at least partially via the activation of IgE-FcεR1 signaling in cardiomyocytes and CFs. Therapeutic strategies targeting the IgE-FcεR1 axis may be effective for managing IgE-mediated cardiac remodeling.

Activity-Induced SUMOylation of Neuronal Nitric Oxide Synthase Is Associated with Plasticity of Synaptic Transmission and Extracellular Signal-Regulated Kinase 1/2 Signaling.

Aims: Neuronal nitric oxide synthase (nNOS) and nitric oxide (NO) signaling have been implicated in learning, memory, and underlying long-lasting synaptic plasticity. In this study, we aimed at detecting whether nNOS is a target protein of SUMOylation in the hippocampus and its contributions to hippocampal long-term potentiation (LTP) of synaptic transmission. Results: We showed that N-methyl-d-aspartate receptor-dependent neuronal activity enhancement induced the attachment of small ubiquitin-like modifier 1 (SUMO1) to nNOS. Protein inhibitor of activated STAT3 (PIAS3) promoted SUMO1 conjugation at K725 and K739 on nNOS, which upregulated NO production and nNOS S1412 phosphorylation (activation). In addition, the N-terminus (amino acids 43-86) of PIAS3 bound nNOS directly. Tat-tagged PIAS3 segment representing amino acids 43-86, a cell-permeable peptide containing PIAS3 residues 43-86, suppressed activity-induced nNOS SUMOylation by disrupting PIAS3-nNOS association. It also decreased LTP-related expression of Arc and brain-derived neurotrophic factor and blocked signaling via extracellular signal-regulated kinase (ERK) 1/2 and Elk-1 in the hippocampus. More importantly, PIAS3-mediated nNOS SUMOylation was required for activity-regulated ERK1/2 activation in nNOS-positive neurons and hippocampal LTP induction. Innovation and Conclusion: These findings indicated that network activity-regulated nNOS SUMOylation underlies excitatory synaptic LTP by facilitating nNOS-NO-ERK1/2 signal cascades.

Chronic inhibition of chemokine receptor CXCR2 attenuates cardiac remodeling and dysfunction in spontaneously hypertensive rats.

System hypertension is a major risk factor for cardiac hypertrophy and heart failure. Our recent findings reveal that the ablation or inhibition of C-X-C chemokine receptor (CXCR) 2 blocks this process in mice; however, it is not clear whether the pharmacological inhibition of CXCR2 attenuates hypertension and subsequent cardiac remodeling in spontaneously hypertensive rats (SHRs). In the present study, we showed that chemokines (CXCL1 and CXCL2) and CXCR2 were significantly upregulated in SHR hearts compared with Wistar-Kyoto rat (WKY) hearts. Moreover, the administration of CXCR2-specific inhibitor N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)-urea (SB225002) in SHRs (at 2 months of age) for an additional 4 months significantly suppressed the elevation of blood pressure, cardiac myocyte hypertrophy, fibrosis, inflammation, and superoxide production and improved heart dysfunction in SHRs compared with vehicle-treated SHRs. SB225002 treatment also reduced established hypertension, cardiac remodeling and contractile dysfunction. Moreover, CXCR2-mediated increases in the recruitment of Mac-2-positive macrophages, proinflammatory cytokines, vascular permeability and ROS production in SHR hearts were markedly attenuated by SB225002. Accordingly, the inhibition of CXCR2 by SB225002 deactivates multiple signaling pathways (AKT/mTOR, ERK1/2, STAT3, calcineurin A, TGF-ß/Smad2/3, NF-κB-p65, and NOX). Our results provide new evidence that the chronic blocking of CXCR2 activation attenuates progression of cardiac hypertrophic remodeling and dysfunction in SHRs. These findings may be of value in understanding the benefits of CXCR2 inhibition for hypertensive cardiac hypertrophy and provide further support for the clinical application of CXCR2 inhibitors for the prevention and treatment of heart failure.

Sonodynamic therapy: A potential treatment for atherosclerosis.

Atherosclerosis (AS), a chronic arterial disease, is one of the major causes of morbidity and mortality worldwide. Several treatment modalities have been demonstrated to be effective in treating AS; however, the mortality rate due to AS remains high. Sonodynamic therapy (SDT) is a promising new treatment using low-intensity ultrasound in combination with sonosensitizers. Although SDT was developed from photodynamic therapy (PDT), it has a stronger tissue-penetrating capability and exhibits a more focused effect on the target lesional site requiring treatment. Furthermore, SDT has been demonstrated to suppress the formation of atheromatous plaques, and it can increase plaque stability both in vitro and in vivo. In this article, we critically summarize the recent literature on SDT, focusing on its possible mechanism of action as well as the existing and newly discovered sonosensitizers and chemotherapeutic agents for the treatment of AS.

Oligomeric amyloid-ß peptide disrupts olfactory information output by impairment of local inhibitory circuits in rat olfactory bulb.

Although early olfactory dysfunction has been found in patients with Alzheimer's disease, the underlying mechanisms remain unclear. In this study, we investigated whether and how oligomeric amyloid-ß peptide (Aß) affects the responses of mitral cells (MCs). We found that oligomeric Aß1-42 increased spontaneous and evoked firing rates but decreased the ratio of evoked to spontaneous firings in MCs. Aß1-42 oligomers showed no impact on the hyperactivity exerted by pharmacological blockage of GABAA receptors, suggesting an involvement of GABAergic inhibitory transmission in Aß1 to 42-induced over-excitability. It was further determined that Aß1-42 oligomers inhibited the frequency of spontaneous inhibitory postsynaptic currents and miniature inhibitory postsynaptic currents, as well as the amplitude of miniature inhibitory postsynaptic currents in MCs. Both recurrent and lateral inhibition of MCs, which are critical for odor discrimination, were also disrupted by Aß1-42 oligomers. The above data indicate that Aß impairs local inhibitory circuits and thereby leads to perturbations of olfactory information output in the olfactory bulb. This study reveals a cellular and synaptic basis of olfactory deficits associated with Alzheimer's disease.