Cellular nucleic acid binding protein facilitates cardiac repair after myocardial infarction by activating ß-catenin signaling.

The regenerative capacity of the adult mammalian heart is limited, while the neonatal heart is an organ with regenerative and proliferative ability. Activating adult cardiomyocytes (CMs) to re-enter the cell cycle is an effective therapeutic method for ischemic heart disease such as myocardial infarction (MI) and heart failure. Here, we aimed to reveal the role and potential mechanisms of cellular nucleic acid binding protein (CNBP) in cardiac regeneration and repair after heart injury. CNBP is highly expressed within 7 days post-birth while decreases significantly with the loss of regenerative ability. In vitro, overexpression of CNBP promoted CM proliferation and survival, whereas knockdown of CNBP inhibited these processes. In vivo, knockdown of CNBP in CMs robustly hindered myocardial regeneration after apical resection in neonatal mice. In adult MI mice, CM-specific CNBP overexpression in the infarct border zone ameliorated myocardial injury in acute stage and facilitated CM proliferation and functional recovery in the long term. Quantitative proteomic analysis with TMT labeling showed that CNBP overexpression promoted the DNA replication, cell cycle progression, and cell division. Mechanically, CNBP overexpression increased the expression of ß-catenin and its downstream target genes CCND1 and c-myc; Furthermore, Luciferase reporter and Chromatin immunoprecipitation (ChIP) assays showed that CNBP could directly bind to the ß-catenin promoter and promote its transcription. CNBP also upregulated the expression of G1/S-related cell cycle genes CCNE1, CDK2, and CDK4. Collectively, our study reveals the positive role of CNBP in promoting cardiac repair after injury, providing a new therapeutic option for the treatment of MI.

Reconstruction for beam blockage of lidar based on generative adversarial networks.

Doppler lidar is an active laser remote sensing instrument. However, beam blockage caused by low-altitude obstacles is a critical factor affecting the quality of lidar data. To reconstruct the line of sight velocities (LOSV) in areas with beam blockages and to evaluate the effectiveness of reconstruction results, the LOSV-filling network (LFnet) approach based on generative adversarial networks (GANs) and an evaluation scheme based on the degree of blockage are proposed in this paper. The LFnet comprises two adversarial models. The first adversarial model captures the structural features of LOSV to output the edge map, and the second adversarial fills in the blockage area using the edge map. We have built a packaged dataset consisting of training, validation and test datasets with mask sets. Then the sensitivity of the reconstruction effectiveness with different shielding conditions is studied, to reveal the mechanism of shielding influencing the reconstruction. A series of indicators were used to evaluate the model's performance, including the traditional indicators and the proposed indicator of root mean square error (RMSE). Finally, LFnet was demonstrated in a practical application in an airport. The complete process of an easterly gust front is reconstructed with RMSE less than 0.85 m/s, which has significance for flight safety.

Estimation of atmospheric refractive index structure constant using an InGaAs/InP single-photon detector.

Remote sensing of atmospheric refractive index structure constant ($\boldsymbol{C}_{\boldsymbol{n}}^2$) using lidar incorporating a single-photon detector (SPD) is proposed. The influence of turbulence on the fiber coupling efficiency with different fiber modes is analyzed. $\boldsymbol{C}_{\boldsymbol{n}}^2$ can be derived from the ratio of the backscattering signals counted on single-mode and multimode fiber-coupling channels of the SPD. In the experiment, by eliminating the shot noise effect on the fluctuation of the ratio, the lowest coupling ratio is used to retrieve $\boldsymbol{C}_{\boldsymbol{n}}^2$ and demonstrated by comparing to the results measured from a large aperture scintillometer (LAS). Good agreement between results from the LAS and the lidar is achieved. The correlation coefficients are 0.90, 0.89, and 0.89, under three different weather conditions.

SIRT3-dependent mitochondrial redox homeostasis mitigates CHK1 inhibition combined with gemcitabine treatment induced cardiotoxicity in hiPSC-CMs and mice.

Administration of CHK1-targeted anticancer therapies is associated with an increased cumulative risk of cardiac complications, which is further amplified when combined with gemcitabine. However, the underlying mechanisms remain elusive. In this study, we generated hiPSC-CMs and murine models to elucidate the mechanisms underlying CHK1 inhibition combined with gemcitabine-induced cardiotoxicity and identify potential targets for cardioprotection. Mice were intraperitoneally injected with 25 mg/kg CHK1 inhibitor AZD7762 and 20 mg/kg gemcitabine for 3 weeks. hiPSC-CMs and NMCMs were incubated with 0.5 uM AZD7762 and 0.1 uM gemcitabine for 24 h. Both pharmacological inhibition or genetic deletion of CHK1 and administration of gemcitabine induced mtROS overproduction and pyroptosis in cardiomyocytes by disrupting mitochondrial respiration, ultimately causing heart atrophy and cardiac dysfunction in mice. These toxic effects were further exacerbated with combination administration. Using mitochondria-targeting sequence-directed vectors to overexpress CHK1 in cardiomyocyte (CM) mitochondria, we identified the localization of CHK1 in CM mitochondria and its crucial role in maintaining mitochondrial redox homeostasis for the first time. Mitochondrial CHK1 function loss mediated the cardiotoxicity induced by AZD7762 and CHK1-knockout. Mechanistically, mitochondrial CHK1 directly phosphorylates SIRT3 and promotes its expression within mitochondria. On the contrary, both AZD7762 or CHK1-knockout and gemcitabine decreased mitochondrial SIRT3 abundance, thus resulting in respiration dysfunction. Further hiPSC-CMs and mice experiments demonstrated that SIRT3 overexpression maintained mitochondrial function while alleviating CM pyroptosis, and thereby improving mice cardiac function. In summary, our results suggest that targeting SIRT3 could represent a novel therapeutic approach for clinical prevention and treatment of cardiotoxicity induced by CHK1 inhibition and gemcitabine.

MNK2-eIF4E axis promotes cardiac repair in the infarcted mouse heart by activating cyclin D1.

Adult mammals have limited potential for cardiac regeneration after injury. In contrast, neonatal mouse heart, up to 7 days post birth, can completely regenerate after injury. Therefore, identifying the key factors promoting the proliferation of endogenous cardiomyocytes (CMs) is a critical step in the development of cardiac regeneration therapies. In our previous study, we predicted that mitogen-activated protein kinase (MAPK) interacting serine/threonine-protein kinase 2 (MNK2) has the potential of promoting regeneration by using phosphoproteomics and iGPS algorithm. Here, we aimed to clarify the role of MNK2 in cardiac regeneration and explore the underlying mechanism. In vitro, MNK2 overexpression promoted, and MNK2 knockdown suppressed cardiomyocyte proliferation. In vivo, inhibition of MNK2 in CMs impaired myocardial regeneration in neonatal mice. In adult myocardial infarcted mice, MNK2 overexpression in CMs in the infarct border zone activated cardiomyocyte proliferation and improved cardiac repair. In CMs, MNK2 binded to eIF4E and regulated its phosphorylation level. Knockdown of eukaryotic translation initiation factor (eIF4E) impaired the proliferation-promoting effect of MNK2 in CMs. MNK2-eIF4E axis stimulated CMs proliferation by activating cyclin D1. Our study demonstrated that MNK2 kinase played a critical role in cardiac regeneration. Over-expression of MNK2 promoted cardiomyocyte proliferation in vitro and in vivo, at least partly, by activating the eIF4E-cyclin D1 axis. This investigation identified a novel target for heart regenerative therapy.

P16ink4a overexpression ameliorates cardiac remodeling of mouse following myocardial infarction via CDK4/pRb pathway.

BACKGROUND: P16ink4a can accumulate in senescent cells and can be induced by different oncogenic stimulations. These functions make p16ink4a a biomarker of senescence and cancer. However, the exact role of p16ink4a remains unclear in cardiovascular disease. This study was aimed to investigate the role of p16ink4a in cardiac remodeling after myocardial infarction (MI). METHODS: In vivo, gain and loss of function experiments using p16ink4a overexpression and knockdown adenovirus were induced to determine the effect of p16ink4a on cardiac structure and function after MI. The in vitro effects of p16ink4a were evaluated by overexpression and knockdown adenovirus of p16ink4a on isolated neonatal mouse cardiac myocytes (NMCMs) and neonatal mouse cardiac fibroblasts (NMCFs). RESULTS: Expression level of p16ink4a was increased after MI and enriched in the infarction area. In vivo, overexpression of p16ink4a protected, while knockdown of p16ink4a worsened cardiac function. In vitro, p16ink4a did not influence the hypertrophy of NMCMs. Overexpression of p16ink4a inhibited the proliferation and migration of NMCFs and reduced the level of collagen I and α-SMA. Consistently, knockdown of p16ink4a in vitro displayed the opposite effects. Further mechanism studies revealed that p16ink4a affected the expression level of cyclin-dependent kinase 4 (CDK4) and phosphorylation of retinoblastoma (pRb), which could be a potential pathway in regulating cardiac remodeling after MI. CONCLUSION: Overexpression of 16ink4a in cardiac fibroblasts can ameliorate cardiac dysfunction and attenuate pathological cardiac remodeling in mice after MI by regulating the p16ink4a/CDK4/pRb pathway.

Dark/bright band of a melting layer detected by coherent Doppler lidar and micro rain radar.

Observation of a melting layer using a 1.55 µm coherent Doppler lidar (CDL) is first presented during a stratiform precipitation event. Simultaneous radar measurements are also performed by co-located 1.24 cm micro rain radar (MRR) and 10.6 cm Doppler weather radar (DWR). As a well-known bright band in radar reflectivity appears during precipitation, an interesting dark band about 160 m below that in lidar backscattering is observed. Due to the absorption effect, the backscattering from raindrops at 1.55 µm is found much weaker than that at short wavelengths usually used in direct detection lidars. However, the CDL provides additional Doppler information which is helpful for melting layer identification. For example, a spectrum bright band with broadened width and sign conversion of skewness is detected in this case. After a deep analysis of the power spectra, the aerosol and precipitation components are separated. The fall speed of hydrometeors given by CDL is found smaller than that of MRR, with the differences of approximately 0.5 m/s and 1.5 m/s for the snow and rainfall, respectively. To illustrate the influence of absorption effect, simulations of the backscatter coefficient and extinction coefficient of aerosol and rainfall are also performed at the wavelength range of 0.3 ∼ 2.2 µm using the Mie theory.

Phosphoproteomic Analysis of Neonatal Regenerative Myocardium Revealed Important Roles of Checkpoint Kinase 1 via Activating Mammalian Target of Rapamycin C1/Ribosomal Protein S6 Kinase b-1 Pathway.

BACKGROUND: In mammals, regenerative therapy after myocardial infarction is hampered by the limited regenerative capacity of adult heart, whereas a transient regenerative capacity is maintained in the neonatal heart. Systemic phosphorylation signaling analysis on ischemic neonatal myocardium might be helpful to identify key pathways involved in heart regeneration. Our aim was to define the kinase-substrate network in ischemic neonatal myocardium and to identify key pathways involved in heart regeneration after ischemic insult. METHODS: Quantitative phosphoproteomics profiling was performed on infarct border zone of neonatal myocardium, and kinase-substrate network analysis revealed 11 kinases with enriched substrates and upregulated phosphorylation levels, including checkpoint kinase 1 (CHK1) kinase. The effect of CHK1 on cardiac regeneration was tested on Institute of Cancer Research CD1 neonatal and adult mice that underwent apical resection or myocardial infarction. RESULTS: In vitro, CHK1 overexpression promoted whereas CHK1 knockdown blunted cardiomyocyte proliferation. In vivo, inhibition of CHK1 hindered myocardial regeneration on resection border zone in neonatal mice. In adult myocardial infarction mice, CHK1 overexpression on infarct border zone upregulated mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway, promoted cardiomyocyte proliferation, and improved cardiac function. Inhibiting mammalian target of rapamycin activity by rapamycin blunted the neonatal cardiomyocyte proliferation induced by CHK1 overexpression in vitro. CONCLUSIONS: Our study indicates that phosphoproteome of neonatal regenerative myocardium could help identify important signaling pathways involved in myocardial regeneration. CHK1 is found to be a key signaling responsible for neonatal regeneration. Myocardial overexpression of CHK1 could improve cardiac regeneration in adult hearts by activating the mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway. Thus, CHK1 might serve as a potential novel target in myocardial repair after myocardial infarction.

Remote sensing of raindrop size distribution using the coherent Doppler lidar.

The coherent Doppler wind lidar (CDL) shows capability in precipitation detection. Retrieval of the raindrop size distribution (DSD) using CDL is still challenging work, as both accurate backscattering cross section at the working wavelength and reflectivity spectrum of raindrop are required. Firstly, the Mie theory and the vectorial complex ray model (VCRM) are applied to calculate backscattering cross section for small spheric raindrops and large oblate raindrops, respectively. Secondly, an iterative deconvolution method is proposed to separate the reflectivity spectrum of raindrop from the lidar power spectrum, which is a superposition of rain and aerosol components. An accompanying aerosol signal model considering the effect of temporal window, from the same height and time, is used to improve the accuracy and robustness of the iteration. In experiment, a co-located micro rain radar (MRR) is used for comparison. Good agreements are obtained despite tremendous differences in wavelength and scattering characteristics. As an example, at 600 m height, the R2 of linear fitting to the mean rain velocity and mean raindrop diameter between CDL and MRR are 0.96 and 0.93, respectively.

Adverse Cerebral Cardiovascular Events Associated With Checkpoint Kinase 1 Inhibitors: A Systemic Review.

ABSTRACT: Checkpoint kinase 1 (CHK1) plays a broad role in regulating the cell cycle process and is involved in the pathogenesis of various malignant tumors. Preclinical and animal studies have shown that CHK1 inhibitors can enhance the cytotoxic effects of radiotherapy and chemotherapy. Currently, CHK1 inhibitors are actively tested in clinical trials. Nonspecific adverse cerebral cardiovascular events were reported after CHK1 inhibitor use; these events need to be monitored and managed carefully during the clinical application of CHK1 inhibitors. To get a better understanding of these, noteworthy adverse cardiovascular events, we systemically searched the PubMed, Cochrane databases, and clinicaltrials.gov, for relevant clinical trials and case reports. A total of 19 studies were identified and included in this review. Among the reported cerebral cardiovascular events, the most common is incident abnormal blood pressure fluctuations (n = 35), followed by incident QTcF prolongation (n = 15), arrhythmia (n = 13, 3 atrial fibrillation and 10 bradycardia), thromboembolic events (n = 9, 6 pulmonary embolisms, 2 stroke, and 1 cerebrovascular event), cardiac troponin T elevation (n = 2), and ischemic chest pain (n = 2). Besides, the estimated incidence for overall cardiovascular events based on the available data is 0.292 (95% confidence interval: 0.096-0.488). CHK1 inhibitors administered in tumor patients on top of conventional therapies can not only enhance the antitumor effects, but also induce adverse cerebral cardiovascular events. It is, therefore, of importance to carefully monitor and manage the CHK1 inhibitor-induced adverse effects on the cerebral cardiovascular system while applying CHK1 inhibitors to tumor patients.

LncRNA FAF inhibits fibrosis induced by angiotensinogen II via the TGFß1-P-Smad2/3 signalling by targeting FGF9 in cardiac fibroblasts.

The dysregulation of Long noncoding RNAs (lncRNAs) has been implicated in many cardiovascular diseases, including cardiac fibrosis. However, the functions and mechanisms of lncRNAs in cardiac fibroblasts (CFs) have not been fully elucidated. First, we observed a correlation between cardiac remodeling (CR) and lncRNA FAF (FGF9-associated factor, termed FAF) expression in the heart. In vitro, we found that the expression of lncRNA FAF was altered in CFs, whereas it behaved inconsistently in cardiomyocytes (CMs). Next, we investigated the effects of lncRNA FAF on angiotensinogen II (Ang II)-induced cardiac fibrosis in neonatal rat CFs and explored the mechanism underlying these effects. In this study, lncRNA FAF was enriched in CFs and was associated with cardiac fibrosis. Upregulation of lncRNA FAF significantly restrained Ang II-induced increases in cell proliferation, differentiation and collagen accumulation of CFs. Moreover, we found that the function of lncRNA FAF was mainly realized through Transforming growth factor ß1 (TGFß1) secretion and then downregulated phosphorylation of Smad2/3. Additional analysis revealed that Fibroblast growth factor 9 (FGF9) is a direct target of lncRNA FAF, as the overexpression of lncRNA FAF could increase the expression of FGF9 and knockdown of the FGF9 expression could attenuate the down-regulation of lncRNA FAF on TGFß1-P-Smad2/3 pathway. Furthermore, knockdown of the FGF9 expression also abolished the inhibitory effect of FAF on fibrosis. In summary, we demonstrated that the overexpression of lncRNA FAF could inhibit fibrosis induced by Ang II via the TGFß1-P-Smad2/3 signalling by targeting FGF9 in CFs.

Identifying cloud, precipitation, windshear, and turbulence by deep analysis of the power spectrum of coherent Doppler wind lidar.

Researches on the atmospheric boundary layer (ABL) need accurate measurements with high temporal and spatial resolutions from a series of different instruments. Here, a method for identifying cloud, precipitation, windshear, and turbulence in the ABL using a single coherent Doppler wind lidar (CDWL) is proposed and demonstrated. Based on deep analysis of the power spectrum of the backscattering signal, multiple lidar products, such as carrier-to-noise (CNR), spectrum width, spectrum skewness, turbulent kinetic energy dissipation rate (TKEDR), and shear intensity are derived for weather identification. Firstly, the cloud is extracted by Haar wavelet covariance transform (HWCT) algorithm based on the CNR after range correction. Secondly, since the spectrum broadening may be due to turbulence, windshear or precipitation, the spectrum skewness is introduced to distinguish the precipitation from two other conditions. Whereas wind velocity is obtained by single peak fitting in clear weather condition, the double-peak fitting is used to retrieve wind and rainfall velocities simultaneously in the precipitation condition. Thirdly, judging from shear intensity and TKEDR, turbulence and windshear are classified. As a double check, the temporal continuity is used. Stable wind variances conditions such as low-level jets are identified as windshear, while arbitrary wind variances conditions are categorized as turbulence. In the field experiment, the method is implemented on a micro-pulse CDWL to provide meteorological services for the 70th anniversary of the China's National Day, in Inner Mongolia, China (43°54'N, 115°58'E). All weather conditions are successfully classified. By comparing lidar results to that of microwave radiometer (MWR), the spectrum skewness is found be more accurate to indicate precipitation than spectrum width or vertical speed. Finally, the parameter relationships and distributions are analyzed statistically in different weather conditions.

Inversion probability enhancement of all-fiber CDWL by noise modeling and robust fitting.

Accurate power spectrum analysis of weak backscattered signals are the primary constraint in long-distance coherent Doppler wind lidar (CDWL) applications. To study the atmospheric boundary layer, an all-fiber CDWL with 300µJ pulse energy is developed. In principle, the coherent detection method can approach the quantum limit sensitivity if the noise in the photodetector output is dominated by the shot noise of the local oscillator. In practice, however, abnormal power spectra occur randomly, resulting in error estimation and low inversion probability. This phenomenon is theoretically analyzed and shown to be due to the leakage of a time-varying DC noise of the balanced detector. Thus, a correction algorithm with accurate noise modeling is proposed and demonstrated. The accuracy of radial velocity, carrier-to-noise ratio (CNR), and spectral width are improved. In wind profiling process, a robust sine-wave fitting algorithm with data quality control is adopted in the velocity-azimuth display (VAD) scanning detection. Finally, in 5-day continuous wind detection, the inversion probability is tremendously enhanced. As an example, it is increased from 8.6% to 52.1% at the height of 4 km.

Simultaneous wind and rainfall detection by power spectrum analysis using a VAD scanning coherent Doppler lidar.

Doppler wind lidar is an effective tool for wind detection with high temporal and spatial resolution. However, precise wind profile measurement under rainy conditions is a challenge, due to the interfering signals from raindrop reflections. In this work, a compact all-fiber coherent Doppler lidar (CDL) at working wavelength of 1.5 µm is applied for simultaneous wind and precipitation detection. The performance of the lidar is validated by comparison with the weather balloons. Thanks to the ability of precise spectrum measurement, both aerosol and rainfall signals can be detected by the CDL under rainy conditions. The spectrum width is used to identify the precipitation events, during which the two-peak Doppler spectrum is observed. The spectrum is fitted by a two-component Gaussian model and two velocities are obtained. By using the velocity-azimuth display (VAD) scanning technique, wind speed and rainfall speed are simultaneously retrieved. The false detection probability of wind speed in the rainy conditions is thus reduced.

Meter-scale spatial-resolution-coherent Doppler wind lidar based on Golay coding.

Generally, the pulse duration of a coherent Doppler wind lidar (CDWL) is shortened to minimize the spatial resolution at the sacrifice of carrier-to-noise ratio, since the peak power of a laser source is limited by the stimulated Brillouin scattering or other nonlinear optical phenomena. To solve this problem, an all-fiber CDWL incorporating Golay coding is proposed and demonstrated. Given the peak power of the laser pulse, the Golay coding method can improve the measuring precision by improving the pulse repetition frequency of the outgoing laser. In the experiment, the Golay coding implementation is optimized by normalizing the intensity of every single pulse of the outgoing laser with a closed-loop feedback, achieving a spatial resolution of 6 m and a temporal resolution of 2 s with a maximum detection range of 552 m. The wind profile in line of sight and the result derived from another noncoding CDWL show good agreement.

Progress of Mitochondrial Function Regulation in Cardiac Regeneration.

Heart failure and myocardial infarction, global health concerns, stem from limited cardiac regeneration post-injury. Myocardial infarction, typically caused by coronary artery blockage, leads to cardiac muscle cell damage, progressing to heart failure. Addressing the adult heart's minimal self-repair capability is crucial, highlighting cardiac regeneration research's importance. Studies reveal a metabolic shift from anaerobic glycolysis to oxidative phosphorylation in neonates as a key factor in impaired cardiac regeneration, with mitochondria being central. The heart's high energy demands rely on a robust mitochondrial network, essential for cellular energy, cardiac health, and regenerative capacity. Mitochondria's influence extends to redox balance regulation, signaling molecule interactions, and apoptosis. Changes in mitochondrial morphology and quantity also impact cardiac cell regeneration. This article reviews mitochondria's multifaceted role in cardiac regeneration, particularly in myocardial infarction and heart failure models. Understanding mitochondrial function in cardiac regeneration aims to enhance myocardial infarction and heart failure treatment methods and insights.

Circular RNA IGF1R Promotes Cardiac Repair via Activating ß-Catenin Signaling by Interacting with DDX5 in Mice after Ischemic Insults.

The potential of circular RNAs (circRNAs) as biomarkers and therapeutic targets is becoming increasingly evident, yet their roles in cardiac regeneration and myocardial renewal remain largely unexplored. Here, we investigated the function of circIGF1R and related mechanisms in cardiac regeneration. Through analysis of circRNA sequencing data from neonatal and adult cardiomyocytes, circRNAs associated with regeneration were identified. Our data showed that circIGF1R expression was high in neonatal hearts, decreased with postnatal maturation, and up-regulated after cardiac injury. The elevation was validated in patients diagnosed with acute myocardial infarction (MI) within 1 week. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and myocardial tissue from mice after apical resection and MI, we observed that circIGF1R overexpression enhanced cardiomyocyte proliferation, reduced apoptosis, and mitigated cardiac dysfunction and fibrosis, while circIGF1R knockdown impeded endogenous cardiac renewal. Mechanistically, we identified circIGF1R binding proteins through circRNA precipitation followed by mass spectrometry. RNA pull-down Western blot and RNA immunoprecipitation demonstrated that circIGF1R directly interacted with DDX5 and augmented its protein level by suppressing ubiquitin-dependent degradation. This subsequently triggered the ß-catenin signaling pathway, leading to the transcriptional activation of cyclin D1 and c-Myc. The roles of circIGF1R and DDX5 in cardiac regeneration were further substantiated through site-directed mutagenesis and rescue experiments. In conclusion, our study highlights the pivotal role of circIGF1R in facilitating heart regeneration and repair after ischemic insults. The circIGF1R/DDX5/ß-catenin axis emerges as a novel therapeutic target for enhancing myocardial repair after MI, offering promising avenues for the development of regenerative therapies.

Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C-Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

BACKGROUND: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. METHODS AND RESULTS: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming. CONCLUSIONS: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

PEX3 promotes regenerative repair after myocardial injury in mice through facilitating plasma membrane localization of ITGB3.

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3ß signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.

Combination of D-dimer level and neutrophil to lymphocyte ratio predicts long-term clinical outcomes in acute coronary syndrome after percutaneous coronary intervention.

BACKGROUND: High D-dimer (DD) is associated with short-term adverse outcomes in patients with acute coronary syndrome (ACS). In ACS patients who underwent percutaneous coronary intervention (PCI), however, the value of DD (or combined with neutrophil to lymphocyte ratio [NLR]) to predict long-term major adverse cardiovascular events (MACEs) has not been fully evaluated. METHODS: Patients diagnosed with ACS and receiving PCI were included. The primary outcome was MACEs. Cox proportional hazards regression and logistic regression were used to illustrate the relationship between clinical risk factors, biomarkers and MACEs. Survival models were developed based on significant factors and evaluated by the Concordance-index (C-index). RESULTS: The final study cohort was comprised of 650 patients (median age, 64 years; 474 males), including 98 (15%) with MACEs during a median follow-up period of 40 months. According to the cut-off value of DD and NLR, the patients were separated into four groups: high DD or nonhigh DD with high or nonhigh NLR. After adjusting for confounding variables, DD (adjusted hazard ratio [aHR]: 2.39, 95% confidence interval [CI]: 1.52-3.76) and NLR (aHR: 2.71, 95% CI: 1.78-4.11) were independently associated with long-term MACEs. Moreover, patients with both high DD and NLR had a significantly higher risk in MACEs when considering patients with nonhigh DD and NLR as reference (aHR: 6.19, 95% CI: 3.30-11.61). The area under curve increased and reached 0.70 in differentiating long-term MACEs when DD and NLR were combined, and survival models incorporating the two exhibited a stronger predictive power (C-index: 0.75). CONCLUSIONS: D-dimer (or combined with NLR) can be used to predict long-term MACEs in ACS patients undergoing PCI.