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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 β1 (TGFβ1) 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 TGFβ1-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 TGFβ1-P-Smad2/3 signalling by targeting FGF9 in CFs.

Background The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine‐protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. Methods and Results The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation– induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte‐specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain‐ and loss‐of‐function experiments using cardiomyocyte‐specific adeno‐associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK‐3β (glycogen synthase kinase‐3β) activity and upregulating β‐catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S‐specific cyclin‐D1, c‐myc (cellular‐myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Conclusions Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.

Abnormalities in programmed cell death (PCD) signaling cascades can be observed in the development and progression of various cardiovascular diseases, such as apoptosis, necrosis, pyroptosis, ferroptosis, and cell death associated with autophagy. Aberrant activation of PCD pathways is a common feature leading to excessive cardiac remodeling and heart failure, involved in the pathogenesis of various cardiovascular diseases. Conversely, timely activation of PCD remodels cardiac structure and function after injury in a spatially or temporally restricted manner and corrects cardiac development similarly. As many cardiovascular diseases exhibit abnormalities in PCD pathways, drugs that can inhibit or modulate PCD may be critical in future therapeutic strategies. In this review, we briefly describe the process of various types of PCD and their roles in the occurrence and development of cardiovascular diseases. We also discuss the interplay between different cell death signaling cascades and summarize pharmaceutical agents targeting key players in cell death signaling pathways that have progressed to clinical trials. Ultimately a better understanding of PCD involved in cardiovascular diseases may lead to new avenues for therapy.

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 was 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 (AUC) 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.

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.

Background: Neonatal heart maintains entire regeneration capacity in a transient regeneration window, but the adult heart loses this function. This process involves numberous core hubs dysregulation of expression and activity that adversely affect the myocardium regeneration ability. Present study screened a functional kinase of serine/threonine-protein kinase 3 (SGK3) in cardiac regeneration after neonatal myocardial infarction (MI) using quantitative phosphoproteomics. Methods: We used quantitative phosphoproteomics data of infarct border zone in newborn heart after MI to identify regeneration related kinases. Gain- and loss-of-function experiments were performed to determine the effect of SGK3 in cardiomyocyte (CM) proliferation and cardiac repair after apical resection (AR) or MI. Pull-down assay and co-immunoprecipitation (Co-IP) experiments were conducted to investigate the direct binding target proteins of SGK3. Results: SGK3 protein expression was highly expressed at postnatal day 1 (P1), reduced at postnatal day 7 (P7) until adult. In vitro, CM proliferation ratio was elevated by SGK3 overexpression, while it was decreased by knockdown of SGK3. In vivo, inhibition of SGK3 shortened the time window of cardiac regeneration after AR in neonatal mice, and overexpression of SGK3 significantly promoted CM proliferation and cardiac repair after MI. Mechanistically, SGK3 could be directly combined with and activated by cyclindependent kinase 9 (CDK9). Inhibition of CDK9 partially abolished the effect of SGK3 on CM proliferation. Moreover, SGK3 could repress GSK-3β activity and increase β-catenin expression. Conclusions: Our study revealed a key role of SGK3 in cardiac regeneration following AR or MI injury, which may reopen a novel therapeutic avenue for MI.

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.

Background: Hepatocyte growth factor (HGF) is an angiogenic cytokine which can promote angiogenesis and inhibit fibrosis. Previous studies have shown that HGF may have significant therapeutic effects on ischaemic diseases, such as ischaemic heart disease and peripheral arterial occlusive disease. Due to insufficient clinical study evidence, we conducted a quantitative meta-analysis of HGF therapy in pigs with myocardial infarction (MI) to provide more reliable evidence for the feasibility and effectiveness of HGF therapy for MI patients. We also analysed the efficacy and characteristics of different gene therapy vectors and drug delivery routes.Methods: PubMed, EMBASE, and the China National Knowledge Infrastructure were searched for randomised studies that corresponded to our subject. The search terms included (hepatocyte growth factor OR HGF) AND (heart failure OR HF OR myocardial infarction OR MI OR AMI OR coronary heart disease OR CHD). The retrieved articles were screened strictly according to the inclusion criteria. The endpoints were the left ventricular ejection fraction (LVEF) and capillary density in the ischaemic regions in the model pigs.Results: A total of nine studies were eventually included in this meta-analysis. Our analysis showed that LVEF (with mean difference [MD]:9.73, 95%CI :8.70, 10.76, P < 0.00001) and capillary density (MD:79.98, 95%CI :24.58,135.39, P=0.005) in the HGF group were significantly higher than those in the control group several weeks after HGF treatment. Further analysis showed that there was no statistically significant difference in the improvement of LVEF caused by intracoronary adenovirus5-mediated HGF (Ad5-HGF) gene transfer and intramyocardial plasmid HGF injection (12.63±3.2 vs 9.4±1.09, P=0.06), while intramyocardial injection of plasmid HGF had a stronger angiogenic capacity than intramyocardial administration of Ad5-HGF and HGF in hydrogel (117.34±27.82 vs 26.45±22.11 vs 11.50±5.28, P＜0.00001).Conclusions: HGF therapy can effectively promote angiogenesis and recovery of cardiac function and is a promising cardiac repair method. Intracoronary Ad5 vector transfer and intramyocardial injection of plasmid vectors can be used as effective means of gene therapy, and hydrogel as a vector also has potential applications.

Background: Previous studies reported that hepatocyte growth factor (HGF) could promote angiogenesis and cardiac function after myocardial infarction (MI) in pigs. However, the results of these studies were controversial. To clarify the therapeutic efficacy of local HGF administration after MI, we performed a systematic review and meta-analysis of data from the pig models, which could provide evidence for the feasibility of clinical HGF application.Methods: PubMed, EMBASE, and China National Knowledge Infrastructure were searched for randomized studies that correspond to our subject. The search terms included (hepatocyte growth factor OR HGF) AND (heart failure OR HF OR myocardial infarction OR MI OR AMI OR coronary heart disease OR CHD). The primary endpoint indicators were identified as the left ventricular ejection fraction (LVEF) and capillaries density. Other parameters reflecting cardiac function and ventricular remodeling were analyzed as secondary indicators, including ventricular volume, infarct size, apoptotic index and others.Results: In total, 9 studies were finally included in the meta-analysis. On comparing the cardiac function indexes, the HGF group was found to be better than the control group in regard to LVEF, stroke volume, left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV). However, no statistically significant differences were found in heart rate. Furthermore, HGF treatment promotes angiogenesis in ischemic areas, which is manifested by increased capillary density. In addition, the HGF group was found to be better than the control group when it comes to infarct size, arteriole densities, and other indicators of cardiac remodeling.Conclusions: HGF treatment can effectively promote cardiac function and cardiac repair including angiogenesis, and this strategy is a promising cardio-protective approach that merits further clinical studies.

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.